U.S. patent application number 13/294318 was filed with the patent office on 2012-05-17 for nampt inhibitors.
This patent application is currently assigned to ABBOTT LABORATORIES. Invention is credited to Rick F. Clark, Michael L. Curtin, Howard R. Heyman, Michael Michaelides, Bryan K. Sorensen, Chris Tse.
Application Number | 20120122924 13/294318 |
Document ID | / |
Family ID | 44999969 |
Filed Date | 2012-05-17 |
United States Patent
Application |
20120122924 |
Kind Code |
A1 |
Curtin; Michael L. ; et
al. |
May 17, 2012 |
NAMPT INHIBITORS
Abstract
Disclosed are compounds which inhibit the activity of NAMPT,
compositions containing the compounds and methods of treating
diseases during which NAMPT is expressed.
Inventors: |
Curtin; Michael L.;
(Pleasant Prairie, WI) ; Sorensen; Bryan K.;
(Antioch, IL) ; Heyman; Howard R.; (Deerfield,
IL) ; Clark; Rick F.; (Gurnee, IL) ;
Michaelides; Michael; (Libertyville, IL) ; Tse;
Chris; (Libertyville, IL) |
Assignee: |
ABBOTT LABORATORIES
Abbott Park
IL
|
Family ID: |
44999969 |
Appl. No.: |
13/294318 |
Filed: |
November 11, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61413646 |
Nov 15, 2010 |
|
|
|
Current U.S.
Class: |
514/314 ;
514/311; 546/144; 546/146 |
Current CPC
Class: |
A61P 25/28 20180101;
A61P 43/00 20180101; C07D 413/12 20130101; C07D 405/12 20130101;
A61P 17/00 20180101; A61P 19/10 20180101; A61P 37/02 20180101; A61P
11/06 20180101; A61P 31/18 20180101; C07D 409/12 20130101; A61P
31/12 20180101; A61P 1/00 20180101; A61P 3/10 20180101; C07D 217/06
20130101; C07D 409/14 20130101; C07D 471/04 20130101; A61P 1/04
20180101; A61P 17/04 20180101; A61P 9/10 20180101; A61P 29/00
20180101; A61P 35/00 20180101; A61P 19/02 20180101; A61P 9/00
20180101; A61P 11/00 20180101; A61P 13/12 20180101; A61P 37/00
20180101; A61P 11/08 20180101; A61P 35/02 20180101; A61P 17/06
20180101; A61P 25/00 20180101; A61P 19/08 20180101; C07D 401/12
20130101 |
Class at
Publication: |
514/314 ;
546/146; 514/311; 546/144 |
International
Class: |
A61K 31/4709 20060101
A61K031/4709; A61K 31/47 20060101 A61K031/47; C07D 487/00 20060101
C07D487/00; A61P 25/28 20060101 A61P025/28; A61P 1/00 20060101
A61P001/00; A61P 3/10 20060101 A61P003/10; A61P 35/00 20060101
A61P035/00; A61P 9/10 20060101 A61P009/10; A61P 37/02 20060101
A61P037/02; A61P 11/06 20060101 A61P011/06; A61P 11/00 20060101
A61P011/00; C07D 217/16 20060101 C07D217/16; A61P 19/10 20060101
A61P019/10 |
Claims
1. A compound of Formula (I), or pharmaceutically acceptable salts
thereof ##STR00015## wherein X.sup.1 and X.sup.2 and X.sup.3 are
CH; or X.sup.1 and X.sup.3 are CH; and X.sup.2 is N; or X.sup.2 and
X.sup.3 are H; and X.sup.1 is N; or X.sup.1 is CR.sup.1; and
X.sup.2 and X.sup.3 are CH; or X.sup.2 is CR.sup.1; and X.sup.1 and
X.sup.3 are CH; or X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are
CH; R.sup.1 is R.sup.3, OR.sup.3, SR.sup.3, S(O)R.sup.3,
SO.sub.2R.sup.3, C(O)R.sup.3, C(O)OR.sup.3, OC(O)R.sup.3,
NHR.sup.3, N(R.sup.3).sub.2, C(O)NH.sub.2, C(O)NHR.sup.3,
C(O)N(R.sup.3).sub.2, NHC(O)R.sup.3, NR.sup.3C(O)R.sup.3,
NHC(O)OR.sup.3, NR.sup.3C(O)OR.sup.3, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.3, SO.sub.2N(R.sup.3).sub.2, NHSO.sub.2R.sup.3,
NR.sup.3SO.sub.2R.sup.3, NHSO.sub.2NHR.sup.3,
NHSO.sub.2N(R.sup.3).sub.2, NR.sup.3SO.sub.2NHR.sup.3,
NR.sup.3SO.sub.2N(R.sup.3).sub.2, C(O)NHSO.sub.2R.sup.3,
NHSO.sub.2NHR.sup.3, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, N.sub.3,
OH, C(O)H, CF.sub.3, C(O)OH, or C(O)NH.sub.2; R.sup.2 is alkyl,
alkenyl, alkynyl, phenyl, heterocyclyl, cycloalkyl, or
cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is
optionally substituted with one or more independently selected
R.sup.4, OR.sup.4, SR.sup.4, S(O)R.sup.4, SO.sub.2R.sup.4,
C(O)R.sup.4, CO(O)R.sup.4, OC(O)R.sup.4, OC(O)OR.sup.4, NH.sub.2,
NHR.sup.4, N(R.sup.4).sub.2, NHC(O)R.sup.4, NR.sup.4C(O)R.sup.4,
NHS(O).sub.2R.sup.4, NR.sup.4S(O).sub.2R.sup.4, NHC(O)OR.sup.4,
NR.sup.4C(O)OR.sup.4, NHC(O)NH.sub.2, NHC(O)NHR.sup.4,
NHC(O)N(R.sup.4).sub.2, NR.sup.4C(O)NHR.sup.4,
NR.sup.4C(O)N(R.sup.4).sub.2, C(O)NH.sub.2, C(O)NHR.sup.4,
C(O)N(R.sup.4).sub.2, C(O)NHOH, C(O)NHOR.sup.4,
C(O)NHSO.sub.2R.sup.4, C(O)NR.sup.4SO.sub.2R.sup.4,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.4, SO.sub.2N(R.sup.4).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
wherein each phenyl is optionally additionally substituted at the
para position with one independently selected R.sup.5,
OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3, SR.sup.5,
S(O)R.sup.5, SO.sub.2R.sup.5, C(O)R.sup.5, CO(O)R.sup.5,
OC(O)R.sup.5, OC(O)OR.sup.5, NH.sub.2, NHR.sup.5, N(R.sup.5).sub.2,
NHC(O)R.sup.5, NR.sup.5C(O)R.sup.5, NHS(O).sub.2R.sup.5,
NR.sup.5S(O).sub.2R.sup.5, NHC(O)OR.sup.5, NR.sup.5C(O)OR.sup.5,
NHC(O)NH.sub.2, NHC(O)NHR.sup.5, NHC(O)N(R.sup.5).sub.2,
NR.sup.5C(O)NHR.sup.5, NR.sup.5C(O)N(R.sup.5).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.5, C(O)N(R.sup.5).sub.2, C(O)NHOH, C(O)NHOR.sup.5,
C(O)NHSO.sub.2R.sup.5, C(O)NR.sup.5SO.sub.2R.sup.5,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.5, SO.sub.2N(R.sup.5).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, Br or I; wherein
each phenyl is optionally additionally substituted with one F;
wherein each heterocyclyl, cycloalkyl, and cycloalkenyl is
optionally substituted with one or more independently selected
R.sup.5, OR.sup.5, SR.sup.5, S(O)R.sup.5, SO.sub.2R.sup.5,
C(O)R.sup.5, CO(O)R.sup.5, OC(O)R.sup.5, OC(O)OR.sup.5, NH.sub.2,
NHR.sup.5, N(R.sup.5).sub.2, NHC(O)R.sup.5, NR.sup.5C(O)R.sup.5,
NHS(O).sub.2R.sup.5, NR.sup.5S(O).sub.2R.sup.5, NHC(O)OR.sup.5,
NR.sup.5C(O)OR.sup.5, NHC(O)NH.sub.2, NHC(O)NHR.sup.5,
NHC(O)N(R.sup.5).sub.2, NR.sup.5C(O)NHR.sup.5,
NR.sup.5C(O)N(R.sup.5).sub.2, C(O)NH.sub.2, C(O)NHR.sup.5,
C(O)N(R.sup.5).sub.2, C(O)NHOH, C(O)NHOR.sup.5,
C(O)NHSO.sub.2R.sup.5, C(O)NR.sup.5SO.sub.2R.sup.5,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.5, SO.sub.2N(R.sup.5).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, CF.sub.3, CF.sub.2CF.sub.3,
OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I; wherein R.sup.2 is
not 4-methylphenyl; R.sup.3 is alkyl, alkenyl, alkynyl, aryl, or
heterocyclyl; wherein each alkyl, alkenyl, and alkynyl is
optionally substituted with one or more independently selected
R.sup.6, OR.sup.6, SR.sup.6, S(O)R.sup.6, SO.sub.2R.sup.6,
C(O)R.sup.6, CO(O)R.sup.6, OC(O)R.sup.6, OC(O)OR.sup.6, NH.sub.2,
NHR.sup.6, N(R.sup.6).sub.2, NHC(O)R.sup.6, NR.sup.6C(O)R.sup.6,
NHS(O).sub.2R.sup.6, NR.sup.6S(O).sub.2R.sup.6, NHC(O)OR.sup.6,
NR.sup.6C(O)OR.sup.6, NHC(O)NH.sub.2, NHC(O)NHR.sup.6,
NHC(O)N(R.sup.6).sub.2, NR.sup.6C(O)NHR.sup.6,
NR.sup.6C(O)N(R.sup.6).sub.2, C(O)NH.sub.2, C(O)NHR.sup.6,
C(O)N(R.sup.6).sub.2, C(O)NHOH, C(O)NHOR.sup.6,
C(O)NHSO.sub.2R.sup.6, C(O)NR.sup.6SO.sub.2R.sup.6,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.6, SO.sub.2N(R.sup.6).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.4 is alkyl, alkenyl, alkynyl, aryl or heterocyclyl; wherein
each alkyl, alkenyl, and alkynyl is optionally substituted with one
or more independently selected R.sup.7, OR.sup.7, SR.sup.7,
S(O)R.sup.7, SO.sub.2R.sup.7, C(O)R.sup.7, CO(O)R.sup.7,
OC(O)R.sup.7, OC(O)OR.sup.7, NH.sub.2, NHR.sup.7, N(R.sup.7).sub.2,
NHC(O)R.sup.7, NR.sup.7C(O)R.sup.7, NHS(O).sub.2R.sup.7,
NR.sup.7S(O).sub.2R.sup.7, NHC(O)OR.sup.7, NR.sup.7C(O)OR.sup.7,
NHC(O)NH.sub.2, NHC(O)NHR.sup.7, NHC(O)N(R.sup.7).sub.2,
NR.sup.7C(O)NHR.sup.7, NR.sup.7C(O)N(R.sup.7).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.7, C(O)N(R.sup.7).sub.2, C(O)NHOH, C(O)NHOR.sup.7,
C(O)NHSO.sub.2R.sup.7, C(O)NR.sup.7SO.sub.2R.sup.7,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
wherein each aryl and heterocycyl is optionally substituted with
one or more independently selected R.sup.8, OR.sup.8, SR.sup.8,
S(O)R.sup.8, SO.sub.2R.sup.8, C(O)R.sup.8, CO(O)R.sup.8,
OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2, NHR.sup.8, N(R.sup.8).sub.2,
NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8, NHS(O).sub.2R.sup.8,
NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8, NR.sup.8C(O)OR.sup.8,
NHC(O)NH.sub.2, NHC(O)NHR.sup.8, NHC(O)N(R.sup.8).sub.2,
NR.sup.8C(O)NHR.sup.8, NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8SO.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.5 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl,
or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is
optionally substituted with one or more independently selected
R.sup.9, OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9,
C(O)R.sup.9, CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2,
NHR.sup.9, N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.6 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl,
or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is
optionally substituted with one or more independently selected
R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10,
NHR.sup.10, N(R.sup.10).sub.2, C(O)R.sup.10, C(O)NH.sub.2,
C(O)NHR.sup.10, C(O)N(R.sup.10).sub.2, NHC(O)R.sup.10,
NR.sup.10C(O)R.sup.10, NHSO.sub.2R.sup.10, NHC(O)OR.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
NHC(O)NH.sub.2, NHC(O)NHR.sup.10, OH, (O), C(O)OH, N.sub.3, CN,
NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or I; R.sup.7 is
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or
cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is
optionally substituted with one or more independently selected
R.sup.11, OR.sup.11, SR.sup.11, S(O)R.sup.11, SO.sub.2R.sup.11,
NHR.sup.11, N(R.sup.11).sub.2, C(O)R.sup.11, C(O)NH.sub.2,
C(O)NHR.sup.11, C(O)N(R.sup.11).sub.2, NHC(O)R.sup.11,
NR.sup.11C(O)R.sup.11, NHSO.sub.2R.sup.11, NHC(O)OR.sup.11,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11, SO.sub.2N(R.sup.11).sub.2,
NHC(O)NH.sub.2, NHC(O)NHR.sup.11, OH, (O), C(O)OH, N.sub.3, CN,
NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or I; R.sup.8 is
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or
cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is
optionally substituted with one or more independently selected
R.sup.12, OR.sup.12, SR.sup.12, S(O)R.sup.12, SO.sub.2R.sup.12,
NHR.sup.12, N(R.sup.12).sub.2, C(O)R.sup.12, C(O)NH.sub.2,
C(O)NHR.sup.12, C(O)N(R.sup.12).sub.2, NHC(O)R.sup.12,
NR.sup.12C(O)R.sup.12, NHSO.sub.2R.sup.12, NHC(O)OR.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
NHC(O)NH.sub.2, NHC(O)NHR.sup.12, OH, (O), C(O)OH, N.sub.3, CN,
NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or I; R.sup.9 is
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or
cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is
optionally substituted with one or more independently selected
OCH.sub.3, aryl, or heterocyclyl; R.sup.10 is alkyl, alkenyl,
alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl; R.sup.11
is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or
cycloalkenyl; R.sup.12 is alkyl, alkenyl, alkynyl, aryl,
heterocyclyl, cycloalkyl, or cycloalkenyl; wherein the cyclic
moieties represented by R.sup.3, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are optionally
substituted with one or more independently selected R.sup.13,
OR.sup.13, SR.sup.13, S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.13 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.14, OR.sup.14, SR.sup.14, S(O)R.sup.14,
SO.sub.2R.sup.14, C(O)R.sup.14, CO(O)R.sup.14, OC(O)R.sup.14,
OC(O)OR.sup.14, NH.sub.2, NHR.sup.14, N(R.sup.14).sub.2,
NHC(O)R.sup.14, NR.sup.14C(O)R.sup.14, NHS(O).sub.2R.sup.14,
NR.sup.14S(O).sub.2R.sup.14, NHC(O)OR.sup.14,
NR.sup.14C(O)OR.sup.14, NHC(O)NH.sub.2, NHC(O)NHR.sup.14,
NHC(O)N(R.sup.14).sub.2, NR.sup.14C(O)NHR.sup.14,
NR.sup.14C(O)N(R.sup.14).sub.2, C(O)NH.sub.2, C(O)NHR.sup.14,
C(O)N(R.sup.14).sub.2, C(O)NHOH, C(O)NHOR.sup.14,
C(O)NHSO.sub.2R.sup.14, C(O)NR.sup.14SO.sub.2R.sup.14,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.14, SO.sub.2N(R.sup.14).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
wherein each aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is
optionally substituted with one or more independently selected
R.sup.15, OR.sup.15, SR.sup.15, S(O)R.sup.15, SO.sub.2R.sup.15,
C(O)R.sup.15, CO(O)R.sup.15, OC(O)R.sup.15, OC(O)OR.sup.15,
NH.sub.2, NHR.sup.15, N(R.sup.15).sub.2, NHC(O)R.sup.15,
NR.sup.15C(O)R.sup.15, NHS(O).sub.2R.sup.15,
NR.sup.15S(O).sub.2R.sup.15, NHC(O)OR.sup.15,
NR.sup.15C(O)OR.sup.15, NHC(O)NH.sub.2, NHC(O)NHR.sup.15,
NHC(O)N(R.sup.15).sub.2, NR.sup.15C(O)NHR.sup.15,
NR.sup.15C(O)N(R.sup.15).sub.2, C(O)NH.sub.2, C(O)NHR.sup.15,
C(O)N(R.sup.15).sub.2, C(O)NHOH, C(O)NHOR.sup.15,
C(O)NHSO.sub.2R.sup.15, C(O)NR.sup.15SO.sub.2R.sup.15,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.15, SO.sub.2N(R.sup.15).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.14 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected NH.sub.2, SO.sub.2NH.sub.2, C(O)H, C(O)OH, OH, (O), CN,
N.sub.3, NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3,
OCF.sub.2CF.sub.3, F, Cl, Br or I; and R.sup.15 is alkyl.
2. A compound having Formula (V), or pharmaceutically acceptable
salts thereof ##STR00016## wherein X.sup.1 and X.sup.2 and X.sup.3
are CH; or X.sup.1 and X.sup.3 are CH; and X.sup.2 is N; or X.sup.2
and X.sup.3 are H; and X.sup.1 is N; or X.sup.1 is CR.sup.1; and
X.sup.2 and X.sup.3 are CH; or X.sup.2 is CR.sup.1; and X.sup.1 and
X.sup.3 are CH; or X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are
CH; R.sup.1 is R.sup.3, OR.sup.3, SR.sup.3, S(O)R.sup.3,
SO.sub.2R.sup.3, C(O)R.sup.3, C(O)OR.sup.3, OC(O)R.sup.3,
NHR.sup.3, N(R.sup.3).sub.2, C(O)NH.sub.2, C(O)NHR.sup.3,
C(O)N(R.sup.3).sub.2, NHC(O)R.sup.3, NR.sup.3C(O)R.sup.3,
NHC(O)OR.sup.3, NR.sup.3C(O)OR.sup.3, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.3, SO.sub.2N(R.sup.3).sub.2, NHSO.sub.2R.sup.3,
NR.sup.3SO.sub.2R.sup.3, NHSO.sub.2NHR.sup.3,
NHSO.sub.2N(R.sup.3).sub.2, NR.sup.3SO.sub.2NHR.sup.3,
NR.sup.3SO.sub.2N(R.sup.3).sub.2, C(O)NHSO.sub.2R.sup.3,
NHSO.sub.2NHR.sup.3, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, N.sub.3,
OH, C(O)H, CF.sub.3, C(O)OH, or C(O)NH.sub.2; R.sup.3 is alkyl,
alkenyl, alkynyl, aryl, or heterocyclyl; wherein each alkyl,
alkenyl, and alkynyl is optionally substituted with one or more
independently selected R.sup.6, OR.sup.6, SR.sup.6, S(O)R.sup.6,
SO.sub.2R.sup.6, C(O)R.sup.6, CO(O)R.sup.6, OC(O)R.sup.6,
OC(O)OR.sup.6, NH.sub.2, NHR.sup.6, N(R.sup.6).sub.2,
NHC(O)R.sup.6, NR.sup.6C(O)R.sup.6, NHS(O).sub.2R.sup.6,
NR.sup.6S(O).sub.2R.sup.6, NHC(O)OR.sup.6, NR.sup.6C(O)OR.sup.6,
NHC(O)NH.sub.2, NHC(O)NHR.sup.6, NHC(O)N(R.sup.6).sub.2,
NR.sup.6C(O)NHR.sup.6, NR.sup.6C(O)N(R.sup.6).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.6, C(O)N(R.sup.6).sub.2, C(O)NHOH, C(O)NHOR.sup.6,
C(O)NHSO.sub.2R.sup.6, C(O)NR.sup.6SO.sub.2R.sup.6,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.6, SO.sub.2N(R.sup.6).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.5 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl,
or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is
optionally substituted with one or more independently selected
R.sup.9, OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9,
C(O)R.sup.9, CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2,
NHR.sup.9, N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.6 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl,
or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is
optionally substituted with one or more independently selected
R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10,
NHR.sup.10, N(R.sup.10).sub.2, C(O)R.sup.10, C(O)NH.sub.2,
C(O)NHR.sup.10, C(O)N(R.sup.10).sub.2, NHC(O)R.sup.10,
NR.sup.10C(O)R.sup.10, NHSO.sub.2R.sup.10, NHC(O)OR.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
NHC(O)NH.sub.2, NHC(O)NHR.sup.10, OH, (O), C(O)OH, N.sub.3, CN,
NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or I; R.sup.9 is
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or
cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is
optionally substituted with one or more independently selected
OCH.sub.3, aryl, or heterocyclyl; R.sup.10 is alkyl, alkenyl,
alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl; wherein
the cyclic moieties represented by R.sup.3, R.sup.5, R.sup.6,
R.sup.9, and R.sup.10, are optionally substituted with one or more
independently selected R.sup.13, OR.sup.13, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13, CO(O)R.sup.13,
OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.3,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.13 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.14, OR.sup.14, SR.sup.14, S(O)R.sup.14,
SO.sub.2R.sup.14C(O)R.sup.14, CO(O)R.sup.14, OC(O)R.sup.14,
OC(O)OR.sup.14, NH.sub.2, NHR.sup.14, N(R.sup.14).sub.2,
NHC(O)R.sup.14, NR.sup.14C(O)R.sup.14, NHS(O).sub.2R.sup.14,
NR.sup.14S(O).sub.2R.sup.14, NHC(O)OR.sup.14,
NR.sup.14C(O)OR.sup.14, NHC(O)NH.sub.2, NHC(O)NHR.sup.14,
NHC(O)N(R.sup.14).sub.2, NR.sup.14C(O)NHR.sup.14,
NR.sup.14C(O)N(R.sup.14).sub.2, C(O)NH.sub.2, C(O)NHR.sup.14,
C(O)N(R.sup.14).sub.2, C(O)NHOH, C(O)NHOR.sup.14,
C(O)NHSO.sub.2R.sup.14, C(O)NR.sup.14SO.sub.2R.sup.14,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.14, SO.sub.2N(R.sup.14).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
wherein each aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is
optionally substituted with one or more independently selected
R.sup.15, OR.sup.15, SR.sup.15, S(O)R.sup.15, SO.sub.2R.sup.15,
C(O)R.sup.15, CO(O)R.sup.15, OC(O)R.sup.15, OC(O)OR.sup.15,
NH.sub.2, NHR.sup.15, N(R.sup.15).sub.2, NHC(O)R.sup.15,
NR.sup.15C(O)R.sup.15, NHS(O).sub.2R.sup.15,
NR.sup.15S(O).sub.2R.sup.15, NHC(O)OR.sup.15,
NR.sup.15C(O)OR.sup.15, NHC(O)NH.sub.2, NHC(O)NHR.sup.15,
NHC(O)N(R.sup.15).sub.2, NR.sup.15C(O)NHR.sup.15,
NR.sup.15C(O)N(R.sup.15).sub.2, C(O)NH.sub.2, C(O)NHR.sup.15,
C(O)N(R.sup.15).sub.2, C(O)NHOH, C(O)NHOR.sup.15,
C(O)NHSO.sub.2R.sup.15, C(O)NR.sup.15SO.sub.2R.sup.15,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.15, SO.sub.2N(R.sup.15).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.14 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected NH.sub.2, SO.sub.2NH.sub.2, C(O)H, C(O)OH, OH, (O), CN,
N.sub.3, NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3,
OCF.sub.2CF.sub.3, F, Cl, Br or I; and R.sup.15 is alkyl.
3. A compound having Formula (IV), or pharmaceutically acceptable
salts thereof ##STR00017## wherein X.sup.1 and X.sup.2 and X.sup.3
are CH; or X.sup.1 and X.sup.3 are CH; and X.sup.2 is N; or X.sup.2
and X.sup.3 are H; and X.sup.1 is N; or X.sup.1 is CR.sup.1; and
X.sup.2 and X.sup.3 are CH; or X.sup.2 is CR.sup.1; and X.sup.1 and
X.sup.3 are CH; or X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are
CH; R.sup.1 is R.sup.3, OR.sup.3, SR.sup.3, S(O)R.sup.3,
SO.sub.2R.sup.3, C(O)R.sup.3, C(O)OR.sup.3, OC(O)R.sup.3,
NHR.sup.3, N(R.sup.3).sub.2, C(O)NH.sub.2, C(O)NHR.sup.3,
C(O)N(R.sup.3).sub.2, NHC(O)R.sup.3, NR.sup.3C(O)R.sup.3,
NHC(O)OR.sup.3, NR.sup.3C(O)OR.sup.3, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.3, SO.sub.2N(R.sup.3).sub.2, NHSO.sub.2R.sup.3,
NR.sup.3SO.sub.2R.sup.3, NHSO.sub.2NHR.sup.3,
NHSO.sub.2N(R.sup.3).sub.2, NR.sup.3SO.sub.2NHR.sup.3,
NR.sup.3SO.sub.2N(R.sup.3).sub.2, C(O)NHSO.sub.2R.sup.3,
NHSO.sub.2NHR.sup.3, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, N.sub.3,
OH, C(O)H, CF.sub.3, C(O)OH, or C(O)NH.sub.2; R.sup.3 is alkyl,
alkenyl, alkynyl, aryl, or heterocyclyl; wherein each alkyl,
alkenyl, and alkynyl is optionally substituted with one or more
independently selected R.sup.6, OR.sup.6, SR.sup.6, S(O)R.sup.6,
SO.sub.2R.sup.6, C(O)R.sup.6, CO(O)R.sup.6, OC(O)R.sup.6,
OC(O)OR.sup.6, NH.sub.2, NHR.sup.6, N(R.sup.6).sub.2,
NHC(O)R.sup.6, NR.sup.6C(O)R.sup.6, NHS(O).sub.2R.sup.6,
NR.sup.6S(O).sub.2R.sup.6, NHC(O)OR.sup.6, NR.sup.6C(O)OR.sup.6,
NHC(O)NH.sub.2, NHC(O)NHR.sup.6, NHC(O)N(R.sup.6).sub.2,
NR.sup.6C(O)NHR.sup.6, NR.sup.6C(O)N(R.sup.6).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.6, C(O)N(R.sup.6).sub.2, C(O)NHOH, C(O)NHOR.sup.6,
C(O)NHSO.sub.2R.sup.6, C(O)NR.sup.6SO.sub.2R.sup.6,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.6, SO.sub.2N(R.sup.6).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.5 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl,
or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is
optionally substituted with one or more independently selected
R.sup.9, OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9,
C(O)R.sup.9, CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2,
NHR.sup.9, N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.6 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl,
or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is
optionally substituted with one or more independently selected
R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10,
NHR.sup.10, N(R.sup.10).sub.2, C(O)R.sup.10, C(O)NH.sub.2,
C(O)NHR.sup.10, C(O)N(R.sup.10).sub.2, NHC(O)R.sup.10,
NR.sup.10C(O)R.sup.10, NHSO.sub.2R.sup.10, NHC(O)OR.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
NHC(O)NH.sub.2, NHC(O)NHR.sup.10, OH, (O), C(O)OH, N.sub.3, CN,
NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or I; R.sup.9 is
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or
cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is
optionally substituted with one or more independently selected
OCH.sub.3, aryl, or heterocyclyl; R.sup.10 is alkyl, alkenyl,
alkynyl, aryl, heterocyclyl, cycloalkyl, or cycloalkenyl; wherein
the cyclic moieties represented by R.sup.3, R.sup.5, R.sup.6,
R.sup.9, and R.sup.10, are optionally substituted with one or more
independently selected R.sup.13, OR.sup.13, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13, CO(O)R.sup.13,
OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.13 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.14, OR.sup.14, SR.sup.14, S(O)R.sup.14,
SO.sub.2R.sup.14, C(O)R.sup.14, CO(O)R.sup.14, OC(O)R.sup.14,
OC(O)OR.sup.14, NH.sub.2, NHR.sup.14, N(R.sup.14).sub.2,
NHC(O)R.sup.14, NR.sup.14C(O)R.sup.14, NHS(O).sub.2R.sup.14,
NR.sup.14S(O).sub.2R.sup.14, NHC(O)OR.sup.14,
NR.sup.14C(O)OR.sup.14, NHC(O)NH.sub.2, NHC(O)NHR.sup.14,
NHC(O)N(R.sup.14).sub.2, NR.sup.14C(O)NHR.sup.14,
NR.sup.14C(O)N(R.sup.14).sub.2, C(O)NH.sub.2, C(O)NHR.sup.14,
C(O)N(R.sup.14).sub.2, C(O)NHOH, C(O)NHOR.sup.14,
C(O)NHSO.sub.2R.sup.14, C(O)NR.sup.14SO.sub.2R.sup.14,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.14, SO.sub.2N(R.sup.14).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
wherein each aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is
optionally substituted with one or more independently selected
R.sup.15, OR.sup.15, SR.sup.15, S(O)R.sup.15, SO.sub.2R.sup.15,
C(O)R.sup.15, CO(O)R.sup.15, OC(O)R.sup.15, OC(O)OR.sup.15,
NH.sub.2, NHR.sup.15, N(R.sup.15).sub.2, NHC(O)R.sup.15,
NR.sup.15C(O)R.sup.15, NHS(O).sub.2R.sup.15,
NR.sup.15S(O).sub.2R.sup.15, NHC(O)OR.sup.15,
NR.sup.15C(O)OR.sup.15, NHC(O)NH.sub.2, NHC(O)NHR.sup.15,
NHC(O)N(R.sup.15).sub.2, NR.sup.15C(O)NHR.sup.15,
NR.sup.15C(O)N(R.sup.15).sub.2, C(O)NH.sub.2, C(O)NHR.sup.15,
C(O)N(R.sup.15).sub.2, C(O)NHOH, C(O)NHOR.sup.15,
C(O)NHSO.sub.2R.sup.15, C(O)NR.sup.15SO.sub.2R.sup.15,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.15, SO.sub.2N(R.sup.15).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.14 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected NH.sub.2, SO.sub.2NH.sub.2, C(O)H, C(O)OH, OH, (O), CN,
N.sub.3, NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3,
OCF.sub.2CF.sub.3, F, Cl, Br or I; and R.sup.15 is alkyl.
4. A compound having Formula (VI), or pharmaceutically acceptable
salts thereof ##STR00018## wherein indicates a single or a double
bond; X.sup.1 and X.sup.2 and X.sup.3 are CH; or X.sup.1 and
X.sup.3 are CH; and X.sup.2 is N; or X.sup.2 and X.sup.3 are H; and
X.sup.1 is N; or X.sup.1 is CR.sup.1; and X.sup.2 and X.sup.3 are
CH; or X.sup.2 is CR.sup.1; and X.sup.1 and X.sup.3 are CH; or
X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are CH; R.sup.1 is
R.sup.3, OR.sup.3, SR.sup.3, S(O)R.sup.3, SO.sub.2R.sup.3,
C(O)R.sup.3, C(O)OR.sup.3, OC(O)R.sup.3, NHR.sup.3,
N(R.sup.3).sub.2, C(O)NH.sub.2, C(O)NHR.sup.3,
C(O)N(R.sup.3).sub.2, NHC(O)R.sup.3, NR.sup.3C(O)R.sup.3,
NHC(O)OR.sup.3, NR.sup.3C(O)OR.sup.3, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.3, SO.sub.2N(R.sup.3).sub.2, NHSO.sub.2R.sup.3,
NR.sup.3SO.sub.2R.sup.3, NHSO.sub.2NHR.sup.3,
NHSO.sub.2N(R.sup.3).sub.2, NR.sup.3SO.sub.2NHR.sup.3,
NR.sup.3SO.sub.2N(R.sup.3).sub.2, C(O)NHSO.sub.2R.sup.3,
NHSO.sub.2NHR.sup.3, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, N.sub.3,
OH, C(O)H, CF.sub.3, C(O)OH, or C(O)NH.sub.2; R.sup.3 is alkyl,
alkenyl, alkynyl, aryl, or heterocyclyl; wherein each alkyl,
alkenyl, and alkynyl is optionally substituted with one or more
independently selected R.sup.6, OR.sup.6, SR.sup.6, S(O)R.sup.6,
SO.sub.2R.sup.6, C(O)R.sup.6, CO(O)R.sup.6, OC(O)R.sup.6,
OC(O)OR.sup.6, NH.sub.2, NHR.sup.6, N(R.sup.6).sub.2,
NHC(O)R.sup.6, NR.sup.6C(O)R.sup.6, NHS(O).sub.2R.sup.6,
NR.sup.6S(O).sub.2R.sup.6, NHC(O)OR.sup.6, NR.sup.6C(O)OR.sup.6,
NHC(O)NH.sub.2, NHC(O)NHR.sup.6, NHC(O)N(R.sup.6).sub.2,
NR.sup.6C(O)NHR.sup.6, NR.sup.6C(O)N(R.sup.6).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.6, C(O)N(R.sup.6).sub.2, C(O)NHOH, C(O)NHOR.sup.6,
C(O)NHSO.sub.2R.sup.6, C(O)NR.sup.6SO.sub.2R.sup.6,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.6, SO.sub.2N(R.sup.6).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.6 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl,
or cycloalkenyl; wherein each alkyl, alkenyl, and alkynyl is
optionally substituted with one or more independently selected
R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10, SO.sub.2R.sup.10,
NHR.sup.10, N(R.sup.10).sub.2, C(O)R.sup.10, C(O)NH.sub.2,
C(O)NHR.sup.10, C(O)N(R.sup.10).sub.2, NHC(O)R.sup.10,
NR.sup.10C(O)R.sup.10, NHSO.sub.2R.sup.10, NHC(O)OR.sup.10,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10, SO.sub.2N(R.sup.10).sub.2,
NHC(O)NH.sub.2, NHC(O)NHR.sup.10, OH, (O), C(O)OH, N.sub.3, CN,
NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or I; R.sup.10 is
alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, or
cycloalkenyl; R.sup.y is R.sup.13, OR.sup.13, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13, CO(O)R.sup.13,
OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.13 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.14, OR.sup.14, SR.sup.14, S(O)R.sup.14,
SO.sub.2R.sup.14, C(O)R.sup.14, CO(O)R.sup.14, OC(O)R.sup.14,
OC(O)OR.sup.14, NH.sub.2, NHR.sup.14, N(R.sup.14).sub.2,
NHC(O)R.sup.14, NR.sup.14C(O)R.sup.14, NHS(O).sub.2R.sup.14,
NR.sup.14S(O).sub.2R.sup.14, NHC(O)OR.sup.14,
NR.sup.14C(O)OR.sup.14, NHC(O)NH.sub.2, NHC(O)NHR.sup.14,
NHC(O)N(R.sup.14).sub.2, NR.sup.14C(O)NHR.sup.14,
NR.sup.14C(O)N(R.sup.14).sub.2, C(O)NH.sub.2, C(O)NHR.sup.14,
C(O)N(R.sup.14).sub.2, C(O)NHOH, C(O)NHOR.sup.14,
C(O)NHSO.sub.2R.sup.14, C(O)NR.sup.14SO.sub.2R.sup.14,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.14, SO.sub.2N(R.sup.14).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
wherein each aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is
optionally substituted with one or more independently selected
R.sup.15, OR.sup.15, SR.sup.15, S(O)R.sup.15, SO.sub.2R.sup.15,
C(O)R.sup.15, CO(O)R.sup.15, OC(O)R.sup.15, OC(O)OR.sup.15,
NH.sub.2, NHR.sup.15, N(R.sup.15).sub.2, NHC(O)R.sup.15,
NR.sup.15C(O)R.sup.15, NHS(O).sub.2R.sup.15,
NR.sup.15S(O).sub.2R.sup.15, NHC(O)OR.sup.15,
NR.sup.15C(O)OR.sup.15, NHC(O)NH.sub.2, NHC(O)NHR.sup.15,
NHC(O)N(R.sup.15).sub.2, NR.sup.15C(O)NHR.sup.15,
NR.sup.15C(O)N(R.sup.15).sub.2, C(O)NH.sub.2, C(O)NHR.sup.15,
C(O)N(R.sup.15).sub.2, C(O)NHOH, C(O)NHOR.sup.15,
C(O)NHSO.sub.2R.sup.15, C(O)NR.sup.15SO.sub.2R.sup.15,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.15, SO.sub.2N(R.sup.15).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.14 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected NH.sub.2, SO.sub.2NH.sub.2, C(O)H, C(O)OH, OH, (O), CN,
N.sub.3, NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3,
OCF.sub.2CF.sub.3, F, Cl, Br or I; and R.sup.15 is alkyl.
5. The compound of any one of claims 1-4, or pharmaceutically
acceptable salts thereof; wherein X.sup.1, X.sup.2, and X.sup.3 are
CH; or X.sup.1 is CR.sup.1 and X.sup.2 and X.sup.3 are CH; or
X.sup.2 is CR.sup.1 and X.sup.1 and X.sup.3 are CH.
6. The compound of any one of claims 1-4, or pharmaceutically
acceptable salts thereof; wherein X.sup.1 and X.sup.3 are CH; and
X.sup.2 is N; or X.sup.2 and X.sup.3 are CH; and X.sup.1 is N.
7. The compound of claim 4, or pharmaceutically acceptable salts
thereof; wherein is a double bond.
8. A compound selected from the group consisting of
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
N-(4-{[4-(pyridin-2-yl)piperazin-1-yl]carbonyl}phenyl)-3,4-dihydr-
oisoquinoline-2(1H)-carboxamide;
6-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide;
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1-
H)-carboxamide;
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1H-
)-carboxamide;
6-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide;
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide;
N-[4-(benzylcarbamoyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
N-{5-[(3-phenylpropyl)carbamoyl]pyridin-2-yl}-3,4-dihydroisoquino-
line-2(1H)-carboxamide;
N-{5-[(3-methylbutyl)carbamoyl]pyridin-2-yl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide;
N-(4-{[1-(3-methylbutyl)-1H-pyrazol-4-yl]carbamoyl}phenyl)-3,4-dihydroiso-
quinoline-2(1H)-carboxamide;
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,6-naphthyridine-
-2(1H)-carboxamide;
6-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide;
N-{4-[(1-benzyl-1H-pyrazol-4-yl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-
-2(1H)-carboxamide;
N-{4-[(2-phenylethyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
7-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoqui-
noline-2(1H)-carboxamide;
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide;
N-{6-[(3-methylbutyl)carbamoyl]pyridin-3-yl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide;
N-(5-{[2-(2-thienyl)ethyl]carbamoyl}pyridin-2-yl)-3,4-dihydroisoquinoline-
-2(1H)-carboxamide;
7-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide;
N-{6-[(3-phenylpropyl)carbamoyl]pyridin-3-yl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide;
N-(6-{[2-(2-thienyl)ethyl]carbamoyl}pyridin-3-yl)-3,4-dihydroisoquinoline-
-2(1H)-carboxamide;
7-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide;
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1-
H)-carboxamide;
N-[4-(2-oxo-2-{[2-(2-thienyl)ethyl]amino}ethyl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide;
N-(4-{2-oxo-2-[(3-phenylpropyl)amino]ethyl}phenyl)-3,4-dihydroisoquinolin-
e-2(1H)-carboxamide;
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1H-
)-carboxamide;
N-(4-{2-[(3-methylbutyl)amino]-2-oxoethyl}phenyl)-3,4-dihydroisoquinoline-
-2(1H)-carboxamide;
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,7-naphthyridine-
-2(1H)-carboxamide;
N-{4-[(4-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
N-{4-[(4-phenylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide;
N-(4-{[3-(2-thienyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide;
N-[4-(1-isobutyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-ca-
rboxamide;
N-[4-(1-propyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline--
2(1H)-carboxamide;
N-{4-[1-((2R)-2-hydroxypropyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide;
N-{4-[1-(3-methylbutyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide;
N-[4-(1-benzyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
N-{4-[(1E)-5-phenylpent-1-en-1-yl]phenyl}-3,4-dihydroisoquinoline-
-2(1H)-carboxamide;
N-[4-(1-ethyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide;
N-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoqui-
noline-2(1H)-carboxamide;
N-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
N-[4-(1-benzoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydr-
oisoquinoline-2(1H)-carboxamide;
N-[4-(1-butyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide;
N-{4-[1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-di-
hydroisoquinoline-2(1H)-carboxamide;
N-[4-(1-isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoq-
uinoline-2(1H)-carboxamide;
N-{4-[1-(3-methylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide;
N-{4-[1-(methylcarbamoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihy-
droisoquinoline-2(1H)-carboxamide; tert-butyl
4-{4-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]phenyl}-3,6-dihydrop-
yridine-1(2H)-carboxylate;
N-[4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide;
N-{4-[1-(isobutylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide;
N-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide;
N-{4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide;
N-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H-
)-carboxamide;
N-{4-[1-(3-methylbutyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydr-
oisoquinoline-2(1H)-carboxamide;
N-[4-(5-propyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-
-carboxamide;
N-[4-(5-benzyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-
-carboxamide;
N-{4-[5-(3-methylbutyl)-1,2,4-oxadiazol-3-yl]phenyl}-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide;
N-hexyl-3,4-dihydroisoquinoline-2(1H)-carboxamide; ethyl
6-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]hexanoate;
N-(4-{2-[(phenylacetyl)amino]ethyl}phenyl)-3,4-dihydroisoquinoline-2(1H)--
carboxamide;
N-{4-[2-(isobutyrylamino)ethyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
N-(4-{[(benzyloxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(-
1H)-carboxamide;
N-(4-{[(4-methoxycyclohexyl)carbonyl]amino}phenyl)-3,4-dihydroisoquinolin-
e-2(1H)-carboxamide;
N-(4-{[(1-acetylpiperidin-4-yl)carbonyl]amino}phenyl)-3,4-dihydroisoquino-
line-2(1H)-carboxamide;
N-(4-{[4-oxo-4-(2-thienyl)butanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide;
N-(4-{[3-(phenylsulfonyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide;
N-{4-[((2R)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide and
N-{4-[((2S)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide; N
N-{4-[((3R)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide and
N-{4-[((3S)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide;
N-{4-[(2,2-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide;
N-{4-[(3,3-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide;
N-[4-(heptanoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
N-{4-[(4,4,4-trifluorobutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide;
N-(4-{[(2-methoxyethoxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide;
N-{4-[((3R)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide and
N-{4-[((3S)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide;
N-(4-{[3-(methylthio)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide;
N-{4-[(cyclopentylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
N-{4-[(cyclohexylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide;
N-{4-[(cyclohexylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide;
N-[4-(benzoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxami-
de;
N-{4-[(phenylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbox-
amide;
N-(4-{[3-(4-aminophenyl)propanoyl]amino}phenyl)-3,4-dihydroisoquino-
line-2(1H)-carboxamide;
N-[4-(3-furoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
N-{4-[(2,5-dimethyl-3-furoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)--
carboxamide;
N-{4-[(3-thienylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
N-{4-[(1H-pyrrol-2-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoli-
ne-2(1H)-carboxamide;
N-{4-[(1,3-thiazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide;
N-{4-[(1H-pyrazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide;
N-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide;
N-{4-[(1,2-oxazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide;
N-{4-[(pyridin-2-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide;
N-{4-[(N,N-dimethyl-beta-alanyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide;
N-(4-{[3-(piperidin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide;
N-{4-[(morpholin-4-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide;
N-(4-{[3-(morpholin-4-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide;
N-(4-{[3-(4-methylpiperazin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoqu-
inoline-2(1H)-carboxamide;
N-[4-(trifluoromethyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
N-{4-[(cyclopentylacetyl)amino]phenyl}-5-[(methylsulfonyl)amino]-3,4-dihy-
droisoquinoline-2(1H)-carboxamide; and pharmaceutically acceptable
salts thereof.
9. The compound of claim 2 selected from the group consisting of
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
N-(4-{[4-(pyridin-2-yl)piperazin-1-yl]carbonyl}phenyl)-3,4-dihydr-
oisoquinoline-2(1H)-carboxamide;
6-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide;
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1-
H)-carboxamide;
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1H-
)-carboxamide;
6-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide;
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide;
N-[4-(benzylcarbamoyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
N-(4-{[1-(3-methylbutyl)-1H-pyrazol-4-yl]carbamoyl}phenyl)-3,4-di-
hydroisoquinoline-2(1H)-carboxamide;
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,6-naphthyridine-
-2(1H)-carboxamide;
6-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide;
N-{4-[(1-benzyl-1H-pyrazol-4-yl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-
-2(1H)-carboxamide;
N-{4-[(2-phenylethyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
7-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoqui-
noline-2(1H)-carboxamide;
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide;
7-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide;
7-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide;
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1-
H)-carboxamide;
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1H-
)-carboxamide;
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,7-naphthyridine-
-2(1H)-carboxamide; and pharmaceutically acceptable salts
thereof.
10. The compound of claim 3 selected from the group consisting of
N-{4-[(4-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
N-{4-[(4-phenylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide;
N-(4-{[3-(2-thienyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide;
N-(4-{[(benzyloxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
N-(4-{[(4-methoxycyclohexyl)carbonyl]amino}phenyl)-3,4-dihydroiso-
quinoline-2(1H)-carboxamide;
N-(4-{[(1-acetylpiperidin-4-yl)carbonyl]amino}phenyl)-3,4-dihydroisoquino-
line-2(1H)-carboxamide;
N-(4-{[4-oxo-4-(2-thienyl)butanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide;
N-(4-{[3-(phenylsulfonyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide;
N-{4-[((2R)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide and
N-{4-[((2S)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide; N
N-{4-[((3R)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide and
N-{4-[((3S)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide;
N-{4-[(2,2-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide;
N-{4-[(3,3-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide;
N-[4-(heptanoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
N-{4-[(4,4,4-trifluorobutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide;
N-(4-{[(2-methoxyethoxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide;
N-{4-[((3R)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide and
N-{4-[((3S)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide;
N-(4-{[3-(methylthio)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide;
N-{4-[(cyclopentylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
N-{4-[(cyclohexylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide;
N-{4-[(cyclohexylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide;
N-[4-(benzoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxami-
de;
N-{4-[(phenylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbox-
amide;
N-(4-{[3-(4-aminophenyl)propanoyl]amino}phenyl)-3,4-dihydroisoquino-
line-2(1H)-carboxamide;
N-[4-(3-furoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
N-{4-[(2,5-dimethyl-3-furoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)--
carboxamide;
N-{4-[(3-thienylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide;
N-{4-[(1H-pyrrol-2-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoli-
ne-2(1H)-carboxamide;
N-{4-[(1,3-thiazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide;
N-{4-[(1H-pyrazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide;
N-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide;
N-{4-[(1,2-oxazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide;
N-{4-[(pyridin-2-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide;
N-{4-[(N,N-dimethyl-beta-alanyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide;
N-(4-{[3-(piperidin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide;
N-{4-[(morpholin-4-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide;
N-(4-{[3-(morpholin-4-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide;
N-(4-{[3-(4-methylpiperazin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoqu-
inoline-2(1H)-carboxamide;
N-{4-[(cyclopentylacetyl)amino]phenyl}-5-[(methylsulfonyl)amino]-3,4-dihy-
droisoquinoline-2(1H)-carboxamide; and pharmaceutically acceptable
salts thereof.
11. The compound of claim 4 selected from the group consisting of
N-[4-(1-benzoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide;
N-[4-(1-butyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide;
N-{4-[1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-di-
hydroisoquinoline-2(1H)-carboxamide;
N-[4-(1-isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoq-
uinoline-2(1H)-carboxamide;
N-{4-[1-(3-methylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide;
N-{4-[1-(methylcarbamoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihy-
droisoquinoline-2(1H)-carboxamide; tert-butyl
4-{4-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]phenyl}-3,6-dihydrop-
yridine-1(2H)-carboxylate;
N-[4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide;
N-{4-[1-(isobutylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide;
N-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide;
N-{4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide;
N-{4-[1-(3-methylbutyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydr-
oisoquinoline-2(1H)-carboxamide; and pharmaceutically acceptable
salts thereof.
12. A composition for treating inflammatory and tissue repair
disorders; particularly rheumatoid arthritis, inflammatory bowel
disease, asthma and COPD (chronic obstructive pulmonary disease),
osteoarthritis, osteoporosis and fibrotic diseases; dermatosis,
including psoriasis, atopic dermatitis and ultra-violet induced
skin damage; autoimmune diseases including systemic lupus
erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing
spondylitis, tissue and organ rejection, Alzheimer's disease,
stroke, athersclerosis, restenosis, diabetes, glomerulonephritis,
cancer, particularly wherein the cancer is selected from breast,
prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas,
leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation
associated with infection and certain viral infections, including
Acquired Immune Deficiency Syndrome (AIDS), adult respiratory
distress syndrome, and ataxia telengiectasia, said composition
comprising an excipient and a therapeutically effective amount of a
compound of claim 1, or pharmaceutically acceptable salts
thereof.
13. A method of treating inflammatory and tissue repair disorders;
particularly rheumatoid arthritis, inflammatory bowel disease,
asthma and COPD (chronic obstructive pulmonary disease),
osteoarthritis, osteoporosis and fibrotic diseases; dermatosis,
including psoriasis, atopic dermatitis and ultra-violet induced
skin damage; autoimmune diseases including systemic lupus
erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing
spondylitis, tissue and organ rejection, Alzheimer's disease,
stroke, athersclerosis, restenosis, diabetes, glomerulonephritis,
cancer, particularly wherein the cancer is selected from breast,
prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas,
leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation
associated with infection and certain viral infections, including
Acquired Immune Deficiency Syndrome (AIDS), adult respiratory
distress syndrome, and ataxia telengiectasia in a patient, said
method comprising administering to the patient a therapeutically
effective amount of a compound of claim 1, or pharmaceutically
acceptable salts thereof.
14. A method of treating inflammatory and tissue repair disorders;
particularly rheumatoid arthritis, inflammatory bowel disease,
asthma and COPD (chronic obstructive pulmonary disease),
osteoarthritis, osteoporosis and fibrotic diseases; dermatosis,
including psoriasis, atopic dermatitis and ultra-violet induced
skin damage; autoimmune diseases including systemic lupus
erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing
spondylitis, tissue and organ rejection, Alzheimer's disease,
stroke, athersclerosis, restenosis, diabetes, glomerulonephritis,
cancer, particularly wherein the cancer is selected from breast,
prostate, lung, colon, cervix, ovary, skin, CNS, bladder, pancreas,
leukemia, lymphoma or Hodgkin's disease, cachexia, inflammation
associated with infection and certain viral infections, including
Acquired Immune Deficiency Syndrome (AIDS), adult respiratory
distress syndrome, and ataxia telengiectasia or spleen cancer in a
patient, said method comprising administering to the patient
therapeutically effective amount of the compound of claim 1, or
pharmaceutically acceptable salts thereof; and a therapeutically
effective amount of one additional therapeutic agent or more than
one additional therapeutic agent.
Description
RELATED APPLICATION INFORMATION
[0001] This application claims priority to U.S. Provisional
Application Ser. No. 61/413,646, filed Nov. 15, 2010, which is
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention pertains to compounds which inhibit the
activity of NAMPT, compositions containing the compounds, and
methods of treating diseases during which NAMPT is expressed.
BACKGROUND OF THE INVENTION
[0003] NAD+ (nicotinamide adenine dinucleotide) is a coenzyme that
plays a critical role in many physiologically essential processes
(Ziegkel, M. Eur. J. Biochem. 267, 1550-1564, 2000). NAD is
necessary for several signaling pathways including among others
poly ADP-ribosylation in DNA repair, mono-ADP-ribosylation in both
the immune system and G-protein-coupled signaling, and NAD is also
required by sirtuins for their deacetylase activity (Garten, A. et
al Trends in Endocrinology and Metabolism, 20, 130-138, 2008).
[0004] NAMPT (also known as pre-B-cell-colony-enhancing factor
(PBEF) and visfatin) is an enzyme that catalyzes the
phosphoribosylation of nicotinamide and is the rate-limiting enzyme
in one of two pathways that salvage NAD.
##STR00001##
[0005] Increasing evidence suggests that NAMPT inhibitors have
potential as anticancer agents. Cancer cells have a higher basal
turnover of NAD and also display higher energy requirements
compared with normal cells. Additionally, increased NAMPT
expression has been reported in colorectal cancer (Van Beijnum, J.
R. et al Int. J. Cancer 101, 118-127, 2002) and NAMPT is involved
in angiogenesis (Kim, S. R. et al. Biochem. Biophys. Res. Commun.
357, 150-156, 2007). Small-molecule inhibitors of NAMPT have been
shown to cause depletion of intracellular NAD+ levels and
ultimately induce tumor cell death (Hansen, C M et al. Anticancer
Res. 20, 42111-4220, 2000) as well as inhibit tumor growth in
xenograft models (Olese, U. H. et al. Mol Cancer Ther. 9,
1609-1617, 2010).
[0006] NAMPT inhibitors also have potential as therapeutic agents
in inflammatory and metabolic disorders (Galli, M. et al Cancer
Res. 70, 8-11, 2010). For example, NAMPT is the predominant enzyme
in T and B lymphocytes. Selective inhibition of NAMPT leads to NAD+
depletion in lymphocytes blocking the expansion that accompanies
autoimmune disease progression whereas cell types expressing the
other NAD+ generating pathways might be spared. A small molecule
NAMPT inhibitor (FK866) has been shown to selectively block
proliferation and induce apoptosis of activated T cells and was
efficacious in animal models of arthritis (collagen-induced
arthritis) (Busso, N. et al. Plos One 3, e2267, 2008). FK866
ameliorated the manifestations of experimental autoimmune
encephalomyelitis (EAE), a model of T-cell mediated autoimmune
disorders. (Bruzzone, S et al. Plos One 4, e7897, 2009). NaMPT
activity increases NF-kB transcriptional activity in human vascular
endothelial cell, resulting in MMP-2 and MMP-9 activation,
suggesting a role for NAMPT inhibitors in the prevention of
inflammatory mediated complications of obesity and type 2 diabetes
(Adya, R. et. Al. Diabetes Care, 31, 758-760, 2008).
SUMMARY OF THE INVENTION
[0007] One embodiment of this invention, therefore, pertains to
compounds or pharmaceutically acceptable salts, which are useful as
inhibitors of NAMPT, the compounds having Formula (I)
##STR00002##
[0008] wherein
[0009] X.sup.1 and X.sup.2 and X.sup.3 are CH; or
[0010] X.sup.1 and X.sup.3 are CH; and X.sup.2 is N; or
[0011] X.sup.2 and X.sup.3 are H; and X.sup.1 is N; or
[0012] X.sup.1 is CR.sup.1; and X.sup.2 and X.sup.3 are CH; or
[0013] X.sup.2 is CR.sup.1; and X.sup.1 and X.sup.3 are CH; or
[0014] X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are CH;
[0015] R.sup.1 is R.sup.3, OR.sup.3, SR.sup.3, S(O)R.sup.3,
SO.sub.2R.sup.3, C(O)R.sup.3, C(O)OR.sup.3, OC(O)R.sup.3,
NHR.sup.3, N(R.sup.3).sub.2, C(O)NH.sub.2, C(O)NHR.sup.3,
C(O)N(R.sup.3).sub.2, NHC(O)R.sup.3, NR.sup.3C(O)R.sup.3,
NHC(O)OR.sup.3, NR.sup.3C(O)OR.sup.3, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.3, SO.sub.2N(R.sup.3).sub.2, NHSO.sub.2R.sup.3,
NR.sup.3SO.sub.2R.sup.3, NHSO.sub.2NHR.sup.3,
NHSO.sub.2N(R.sup.3).sub.2, NR.sup.3SO.sub.2NHR.sup.3,
NR.sup.3SO.sub.2N(R.sup.3).sub.2, C(O)NHSO.sub.2R.sup.3,
NHSO.sub.2NHR.sup.3, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, N.sub.3,
OH, C(O)H, CF.sub.3, C(O)OH, or C(O)NH.sub.2;
[0016] R.sup.2 is alkyl, alkenyl, alkynyl, phenyl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.4, OR.sup.4, SR.sup.4, S(O)R.sup.4, SO.sub.2R.sup.4,
C(O)R.sup.4, CO(O)R.sup.4, OC(O)R.sup.4, OC(O)OR.sup.4, NH.sub.2,
NHR.sup.4, N(R.sup.4).sub.2, NHC(O)R.sup.4, NR.sup.4C(O)R.sup.4,
NHS(O).sub.2R.sup.4, NR.sup.4S(O).sub.2R.sup.4, NHC(O)OR.sup.4,
NR.sup.4C(O)OR.sup.4, NHC(O)NH.sub.2, NHC(O)NHR.sup.4,
NHC(O)N(R.sup.4).sub.2, NR.sup.4C(O)NHR.sup.4,
NR.sup.4C(O)N(R.sup.4).sub.2, C(O)NH.sub.2, C(O)NHR.sup.4,
C(O)N(R.sup.4).sub.2, C(O)NHOH, C(O)NHOR.sup.4,
C(O)NHSO.sub.2R.sup.4, C(O)NR.sup.4SO.sub.2R.sup.4,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.4, SO.sub.2N(R.sup.4).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
wherein each phenyl is optionally additionally substituted at the
para position with one independently selected R.sup.5,
OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3, SR.sup.5,
S(O)R.sup.5, SO.sub.2R.sup.5, C(O)R.sup.5, CO(O)R.sup.5,
OC(O)R.sup.5, OC(O)OR.sup.5, NH.sub.2, NHR.sup.5, N(R.sup.5).sub.2,
NHC(O)R.sup.5, NR.sup.5C(O)R.sup.5, NHS(O).sub.2R.sup.5,
NR.sup.5S(O).sub.2R.sup.5, NHC(O)OR.sup.5, NR.sup.5C(O)OR.sup.5,
NHC(O)NH.sub.2, NHC(O)NHR.sup.5, NHC(O)N(R.sup.5).sub.2,
NR.sup.5C(O)NHR.sup.5, NR.sup.5C(O)N(R.sup.5).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.5, C(O)N(R.sup.5).sub.2, C(O)NHOH, C(O)NHOR.sup.5,
C(O)NHSO.sub.2R.sup.5, C(O)NR.sup.5SO.sub.2R.sup.5,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.5, SO.sub.2N(R.sup.5).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, Br or I; wherein
each phenyl is optionally additionally substituted with one F;
wherein each heterocyclyl, cycloalkyl, and cycloalkenyl is
optionally substituted with one or more independently selected
R.sup.5, OR.sup.5, SR.sup.5, S(O)R.sup.5, SO.sub.2R.sup.5,
C(O)R.sup.5, CO(O)R.sup.5, OC(O)R.sup.5, OC(O)OR.sup.5, NH.sub.2,
NHR.sup.5, N(R.sup.5).sub.2, NHC(O)R.sup.5, NR.sup.5C(O)R.sup.5,
NHS(O).sub.2R.sup.5, NR.sup.5S(O).sub.2R.sup.5, NHC(O)OR.sup.5,
NR.sup.5C(O)OR.sup.5, NHC(O)NH.sub.2, NHC(O)NHR.sup.5,
NHC(O)N(R.sup.5).sub.2, NR.sup.5C(O)NHR.sup.5,
NR.sup.5C(O)N(R.sup.5).sub.2, C(O)NH.sub.2, C(O)NHR.sup.5,
C(O)N(R.sup.5).sub.2, C(O)NHOH, C(O)NHOR.sup.5,
C(O)NHSO.sub.2R.sup.5, C(O)NR.sup.5SO.sub.2R.sup.5,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.5, SO.sub.2N(R.sup.5).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, CF.sub.3, CF.sub.2CF.sub.3,
OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I; wherein R.sup.2 is
not 4-methylphenyl;
[0017] R.sup.3 is alkyl, alkenyl, alkynyl, aryl, or heterocyclyl;
wherein each alkyl, alkenyl, and alkynyl is optionally substituted
with one or more independently selected R.sup.6, OR.sup.6,
SR.sup.6, S(O)R.sup.6, SO.sub.2R.sup.6, C(O)R.sup.6, CO(O)R.sup.6,
OC(O)R.sup.6, OC(O)OR.sup.6, NH.sub.2, NHR.sup.6, N(R.sup.6).sub.2,
NHC(O)R.sup.6, NR.sup.6C(O)R.sup.6, NHS(O).sub.2R.sup.6,
NR.sup.6S(O).sub.2R.sup.6, NHC(O)OR.sup.6, NR.sup.6C(O)OR.sup.6,
NHC(O)NH.sub.2, NHC(O)NHR.sup.6, NHC(O)N(R.sup.6).sub.2,
NR.sup.6C(O)NHR.sup.6, NR.sup.6C(O)N(R.sup.6).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.6, C(O)N(R.sup.6).sub.2, C(O)NHOH, C(O)NHOR.sup.6,
C(O)NHSO.sub.2R.sup.6, C(O)NR.sup.6SO.sub.2R.sup.6,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.6, SO.sub.2N(R.sup.6).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0018] R.sup.4 is alkyl, alkenyl, alkynyl, aryl or heterocyclyl;
wherein each alkyl, alkenyl, and alkynyl is optionally substituted
with one or more independently selected R.sup.7, OR.sup.7,
SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7, C(O)R.sup.7, CO(O)R.sup.7,
OC(O)R.sup.7, OC(O)OR.sup.7, NH.sub.2, NHR.sup.7, N(R.sup.7).sub.2,
NHC(O)R.sup.7, NR.sup.7C(O)R.sup.7, NHS(O).sub.2R.sup.7,
NR.sup.7S(O).sub.2R.sup.7, NHC(O)OR.sup.7, NR.sup.7C(O)OR.sup.7,
NHC(O)NH.sub.2, NHC(O)NHR.sup.7, NHC(O)N(R.sup.7).sub.2,
NR.sup.7C(O)NHR.sup.7, NR.sup.7C(O)N(R.sup.7).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.7, C(O)N(R.sup.7).sub.2, C(O)NHOH, C(O)NHOR.sup.7,
C(O)NHSO.sub.2R.sup.7, C(O)NR.sup.7SO.sub.2R.sup.7,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
wherein each aryl and heterocycyl is optionally substituted with
one or more independently selected R.sup.8, OR.sup.8, SR.sup.8,
S(O)R.sup.8, SO.sub.2R.sup.8, C(O)R.sup.8, CO(O)R.sup.8,
OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2, NHR.sup.8, N(R.sup.8).sub.2,
NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8, NHS(O).sub.2R.sup.8,
NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8, NR.sup.8C(O)OR.sup.8,
NHC(O)NH.sub.2, NHC(O)NHR.sup.8, NHC(O)N(R.sup.8).sub.2,
NR.sup.8C(O)NHR.sup.8, NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8SO.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0019] R.sup.5 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.9, OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9,
C(O)R.sup.9, CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2,
NHR.sup.9, N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0020] R.sup.6 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10,
SO.sub.2R.sup.10, NHR.sup.10, N(R.sup.10).sub.2, C(O)R.sup.10,
C(O)NH.sub.2, C(O)NHR.sup.10, C(O)N(R.sup.10).sub.2,
NHC(O)R.sup.10, NR.sup.10C(O)R.sup.10, NHSO.sub.2R.sup.10,
NHC(O)OR.sup.10, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10,
SO.sub.2N(R.sup.10).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.10, OH,
(O), C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F,
Cl, Br or I;
[0021] R.sup.7 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.11, OR.sup.11, SR.sup.11, S(O)R.sup.11,
SO.sub.2R.sup.11, NHR.sup.11, N(R.sup.11).sub.2, C(O)R.sup.11,
C(O)NH.sub.2, C(O)NHR.sup.11, C(O)N(R.sup.11).sub.2,
NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11, NHSO.sub.2R.sup.11,
NHC(O)OR.sup.11, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11,
SO.sub.2N(R.sup.11).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.11, OH,
(O), C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F,
Cl, Br or I;
[0022] R.sup.8 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.12, OR.sup.12, SR.sup.12, S(O)R.sup.12,
SO.sub.2R.sup.12, NHR.sup.12, N(R.sup.12).sub.2, C(O)R.sup.12,
C(O)NH.sub.2, C(O)NHR.sup.12, C(O)N(R.sup.12).sub.2,
NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12, NHSO.sub.2R.sup.12,
NHC(O)OR.sup.12, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12,
SO.sub.2N(R.sup.12).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.12, OH,
(O), C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F,
Cl, Br or I;
[0023] R.sup.9 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected OCH.sub.3, aryl, or heterocyclyl;
[0024] R.sup.10 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl;
[0025] R.sup.11 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl;
[0026] R.sup.12 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl;
[0027] wherein the cyclic moieties represented by R.sup.3, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, and
R.sup.12 are optionally substituted with one or more independently
selected R.sup.13, OR.sup.13, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, C(O)R.sup.13, CO(O)R.sup.13, OC(O)R.sup.13,
OC(O)OR.sup.13, NH.sub.2, NHR.sup.13, N(R.sup.13).sub.2,
NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13, NHS(O).sub.2R.sup.13,
NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0028] R.sup.13 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.14, OR.sup.14, SR.sup.14, S(O)R.sup.14,
SO.sub.2R.sup.14, C(O)R.sup.14, CO(O)R.sup.14, OC(O)R.sup.14,
OC(O)OR.sup.14, NH.sub.2, NHR.sup.14, N(R.sup.14).sub.2,
NHC(O)R.sup.14, NR.sup.14C(O)R.sup.14, NHS(O).sub.2R.sup.14,
NR.sup.14S(O).sub.2R.sup.14, NHC(O)OR.sup.14,
NR.sup.14C(O)OR.sup.14, NHC(O)NH.sub.2, NHC(O)NHR.sup.14,
NHC(O)N(R.sup.14).sub.2, NR.sup.14C(O)NHR.sup.14,
NR.sup.14C(O)N(R.sup.14).sub.2, C(O)NH.sub.2, C(O)NHR.sup.14,
C(O)N(R.sup.14).sub.2, C(O)NHOH, C(O)NHOR.sup.14,
C(O)NHSO.sub.2R.sup.14, C(O)NR.sup.14SO.sub.2R.sup.14,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.14, SO.sub.2N(R.sup.14).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
wherein each aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is
optionally substituted with one or more independently selected
R.sup.15, OR.sup.15, SR.sup.15, S(O)R.sup.15, SO.sub.2R.sup.15,
C(O)R.sup.15, CO(O)R.sup.15, OC(O)R.sup.15, OC(O)OR.sup.15,
NH.sub.2, NHR.sup.15, N(R.sup.15).sub.2, NHC(O)R.sup.15,
NR.sup.15C(O)R.sup.15, NHS(O).sub.2R.sup.15,
NR.sup.15S(O).sub.2R.sup.15, NHC(O)OR.sup.15,
NR.sup.15C(O)OR.sup.15, NHC(O)NH.sub.2, NHC(O)NHR.sup.15,
NHC(O)N(R.sup.15).sub.2, NR.sup.15C(O)NHR.sup.15,
NR.sup.15C(O)N(R.sup.15).sub.2, C(O)NH.sub.2, C(O)NHR.sup.15,
C(O)N(R.sup.15).sub.2, C(O)NHOH, C(O)NHOR.sup.15,
C(O)NHSO.sub.2R.sup.15, C(O)NR.sup.15SO.sub.2R.sup.15,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.15, SO.sub.2N(R.sup.15).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0029] R.sup.14 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected NH.sub.2, SO.sub.2NH.sub.2, C(O)H, C(O)OH, OH, (O), CN,
N.sub.3, NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3,
OCF.sub.2CF.sub.3, F, Cl, Br or I; and
[0030] R.sup.15 is alkyl.
[0031] Another embodiment of this invention pertains to compounds
or pharmaceutically acceptable salts thereof; which are useful as
inhibitors of NAMPT, the compounds having Formula (V)
##STR00003##
[0032] wherein
[0033] X.sup.1 and X.sup.2 and X.sup.3 are CH; or
[0034] X.sup.1 and X.sup.3 are CH; and X.sup.2 is N; or
[0035] X.sup.2 and X.sup.3 are H; and X.sup.1 is N; or
[0036] X.sup.1 is CR.sup.1; and X.sup.2 and X.sup.3 are CH; or
[0037] X.sup.2 is CR.sup.1; and X.sup.1 and X.sup.3 are CH; or
[0038] X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are CH;
[0039] R.sup.1 is R.sup.3, OR.sup.3, SR.sup.3, S(O)R.sup.3,
SO.sub.2R.sup.3, C(O)R.sup.3, C(O)OR.sup.3, OC(O)R.sup.3,
NHR.sup.3, N(R.sup.3).sub.2, C(O)NH.sub.2, C(O)NHR.sup.3,
C(O)N(R.sup.3).sub.2, NHC(O)R.sup.3, NR.sup.3C(O)R.sup.3,
NHC(O)OR.sup.3, NR.sup.3C(O)OR.sup.3, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.3, SO.sub.2N(R.sup.3).sub.2, NHSO.sub.2R.sup.3,
NR.sup.3SO.sub.2R.sup.3, NHSO.sub.2NHR.sup.3,
NHSO.sub.2N(R.sup.3).sub.2, NR.sup.3SO.sub.2NHR.sup.3,
NR.sup.3SO.sub.2N(R.sup.3).sub.2, C(O)NHSO.sub.2R.sup.3,
NHSO.sub.2NHR.sup.3, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, N.sub.3,
OH, C(O)H, CF.sub.3, C(O)OH, or C(O)NH.sub.2;
[0040] R.sup.3 is alkyl, alkenyl, alkynyl, aryl, or heterocyclyl;
wherein each alkyl, alkenyl, and alkynyl is optionally substituted
with one or more independently selected R.sup.6, OR.sup.6,
SR.sup.6, S(O)R.sup.6, SO.sub.2R.sup.6, C(O)R.sup.6, CO(O)R.sup.6,
OC(O)R.sup.6, OC(O)OR.sup.6, NH.sub.2, NHR.sup.6, N(R.sup.6).sub.2,
NHC(O)R.sup.6, NR.sup.6C(O)R.sup.6, NHS(O).sub.2R.sup.6,
NR.sup.6S(O).sub.2R.sup.6, NHC(O)OR.sup.6, NR.sup.6C(O)OR.sup.6,
NHC(O)NH.sub.2, NHC(O)NHR.sup.6, NHC(O)N(R.sup.6).sub.2,
NR.sup.6C(O)NHR.sup.6, NR.sup.6C(O)N(R.sup.6).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.6, C(O)N(R.sup.6).sub.2, C(O)NHOH, C(O)NHOR.sup.6,
C(O)NHSO.sub.2R.sup.6, C(O)NR.sup.6SO.sub.2R.sup.6,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.6, SO.sub.2N(R.sup.6).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0041] R.sup.5 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.9, OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9,
C(O)R.sup.9, CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2,
NHR.sup.9, N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0042] R.sup.6 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10,
SO.sub.2R.sup.10, NHR.sup.10, N(R.sup.10).sub.2, C(O)R.sup.10,
C(O)NH.sub.2, C(O)NHR.sup.10, C(O)N(R.sup.10).sub.2,
NHC(O)R.sup.10, NR.sup.10C(O)R.sup.10, NHSO.sub.2R.sup.10,
NHC(O)OR.sup.10, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10,
SO.sub.2N(R.sup.10).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.10, OH,
(O), C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F,
Cl, Br or I;
[0043] R.sup.9 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected OCH.sub.3, aryl, or heterocyclyl;
[0044] R.sup.10 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl;
[0045] wherein the cyclic moieties represented by R.sup.3, R.sup.5,
R.sup.6, R.sup.9, and R.sup.10, are optionally substituted with one
or more independently selected R.sup.13, OR.sup.13, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13, CO(O)R.sup.13,
OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0046] R.sup.13 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.14, OR.sup.14, SR.sup.14, S(O)R.sup.14,
SO.sub.2R.sup.14, C(O)R.sup.14, CO(O)R.sup.14, OC(O)R.sup.14,
OC(O)OR.sup.14, NH.sub.2, NHR.sup.14, N(R.sup.14).sub.2,
NHC(O)R.sup.14, NR.sup.14C(O)R.sup.14, NHS(O).sub.2R.sup.14,
NR.sup.14S(O).sub.2R.sup.14, NHC(O)OR.sup.14,
NR.sup.14C(O)OR.sup.14, NHC(O)NH.sub.2, NHC(O)NHR.sup.14,
NHC(O)N(R.sup.14).sub.2, NR.sup.14C(O)NHR.sup.14,
NR.sup.14C(O)N(R.sup.14).sub.2, C(O)NH.sub.2, C(O)NHR.sup.14,
C(O)N(R.sup.14).sub.2, C(O)NHOH, C(O)NHOR.sup.14,
C(O)NHSO.sub.2R.sup.14, C(O)NR.sup.14SO.sub.2R.sup.14,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.14, SO.sub.2N(R.sup.14).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
wherein each aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is
optionally substituted with one or more independently selected
R.sup.15, OR.sup.15, SR.sup.15, S(O)R.sup.15, SO.sub.2R.sup.15,
C(O)R.sup.15, CO(O)R.sup.15, OC(O)R.sup.15, OC(O)OR.sup.15,
NH.sub.2, NHR.sup.15, N(R.sup.15).sub.2, NHC(O)R.sup.15,
NR.sup.15C(O)R.sup.15, NHS(O).sub.2R.sup.15,
NR.sup.15S(O).sub.2R.sup.15, NHC(O)OR.sup.15,
NR.sup.15C(O)OR.sup.15, NHC(O)NH.sub.2, NHC(O)NHR.sup.15,
NHC(O)N(R.sup.15).sub.2, NR.sup.15C(O)NHR.sup.15,
NR.sup.15C(O)N(R.sup.15).sub.2, C(O)NH.sub.2, C(O)NHR.sup.15,
C(O)N(R.sup.15).sub.2, C(O)NHOH, C(O)NHOR.sup.15,
C(O)NHSO.sub.2R.sup.15, C(O)NR.sup.15SO.sub.2R.sup.15,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.15, SO.sub.2N(R.sup.15).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0047] R.sup.14 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected NH.sub.2, SO.sub.2NH.sub.2, C(O)H, C(O)OH, OH, (O), CN,
N.sub.3, NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3,
OCF.sub.2CF.sub.3, F, Cl, Br or I; and
[0048] R.sup.15 is alkyl.
[0049] Another embodiment of this invention pertains to compounds
or pharmaceutically acceptable salts thereof; which are useful as
inhibitors of NAMPT, the compounds having Formula (IV)
##STR00004##
[0050] wherein
[0051] X.sup.1 and X.sup.2 and X.sup.3 are CH; or
[0052] X.sup.1 and X.sup.3 are CH; and X.sup.2 is N; or
[0053] X.sup.2 and X.sup.3 are H; and X.sup.1 is N; or
[0054] X.sup.1 is CR.sup.1; and X.sup.2 and X.sup.3 are CH; or
[0055] X.sup.2 is CR.sup.1; and X.sup.1 and X.sup.3 are CH; or
[0056] X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are CH;
[0057] R.sup.1 is R.sup.3, OR.sup.3, SR.sup.3, S(O)R.sup.3,
SO.sub.2R.sup.3, C(O)R.sup.3, C(O)OR.sup.3, OC(O)R.sup.3,
NHR.sup.3, N(R.sup.3).sub.2, C(O)NH.sub.2, C(O)NHR.sup.3,
C(O)N(R.sup.3).sub.2, NHC(O)R.sup.3, NR.sup.3C(O)R.sup.3,
NHC(O)OR.sup.3, NR.sup.3C(O)OR.sup.3, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.3, SO.sub.2N(R.sup.3).sub.2, NHSO.sub.2R.sup.3,
NR.sup.3SO.sub.2R.sup.3, NHSO.sub.2NHR.sup.3,
NHSO.sub.2N(R.sup.3).sub.2, NR.sup.3SO.sub.2NHR.sup.3,
NR.sup.3SO.sub.2N(R.sup.3).sub.2, C(O)NHSO.sub.2R.sup.3,
NHSO.sub.2NHR.sup.3, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, N.sub.3,
OH, C(O)H, CF.sub.3, C(O)OH, or C(O)NH.sub.2;
[0058] R.sup.3 is alkyl, alkenyl, alkynyl, aryl, or heterocyclyl;
wherein each alkyl, alkenyl, and alkynyl is optionally substituted
with one or more independently selected R.sup.6, OR.sup.6,
SR.sup.6, S(O)R.sup.6, SO.sub.2R.sup.6, C(O)R.sup.6, CO(O)R.sup.6,
OC(O)R.sup.6, OC(O)OR.sup.6, NH.sub.2, NHR.sup.6, N(R.sup.6).sub.2,
NHC(O)R.sup.6, NR.sup.6C(O)R.sup.6, NHS(O).sub.2R.sup.6,
NR.sup.6S(O).sub.2R.sup.6, NHC(O)OR.sup.6, NR.sup.6C(O)OR.sup.6,
NHC(O)NH.sub.2, NHC(O)NHR.sup.6, NHC(O)N(R.sup.6).sub.2,
NR.sup.6C(O)NHR.sup.6, NR.sup.6C(O)N(R.sup.6).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.6, C(O)N(R.sup.6).sub.2, C(O)NHOH, C(O)NHOR.sup.6,
C(O)NHSO.sub.2R.sup.6, C(O)NR.sup.6SO.sub.2R.sup.6,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.6, SO.sub.2N(R.sup.6).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0059] R.sup.5 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.9, OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9,
C(O)R.sup.9, CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2,
NHR.sup.9, N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0060] R.sup.6 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10,
SO.sub.2R.sup.10, NHR.sup.10, N(R.sup.10).sub.2, C(O)R.sup.10,
C(O)NH.sub.2, C(O)NHR.sup.10, C(O)N(R.sup.10).sub.2,
NHC(O)R.sup.10, NR.sup.10C(O)R.sup.10, NHSO.sub.2R.sup.10,
NHC(O)OR.sup.10, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10,
SO.sub.2N(R.sup.10).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.10, OH,
(O), C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F,
Cl, Br or I;
[0061] R.sup.9 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected OCH.sub.3, aryl, or heterocyclyl;
[0062] R.sup.10 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl;
[0063] wherein the cyclic moieties represented by R.sup.3, R.sup.5,
R.sup.6, R.sup.9, and R.sup.10, are optionally substituted with one
or more independently selected R.sup.13, OR.sup.13, SR.sup.13,
S(O)R.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13, CO(O)R.sup.13,
OC(O)R.sup.13, OC(O)OR.sup.13, NH.sub.2, NHR.sup.13,
N(R.sup.13).sub.2, NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13,
NHS(O).sub.2R.sup.13, NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0064] R.sup.13 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.14, OR.sup.14, SR.sup.14, S(O)R.sup.14,
SO.sub.2R.sup.14, C(O)R.sup.14, CO(O)R.sup.14, OC(O)R.sup.14,
OC(O)OR.sup.14, NH.sub.2, NHR.sup.14, N(R.sup.14).sub.2,
NHC(O)R.sup.14, NR.sup.14C(O)R.sup.14, NHS(O).sub.2R.sup.14,
NR.sup.14S(O).sub.2R.sup.14, NHC(O)OR.sup.14,
NR.sup.14C(O)OR.sup.14, NHC(O)NH.sub.2, NHC(O)NHR.sup.14,
NHC(O)N(R.sup.14).sub.2, NR.sup.14C(O)NHR.sup.14,
NR.sup.14C(O)N(R.sup.14).sub.2, C(O)NH.sub.2, C(O)NHR.sup.14,
C(O)N(R.sup.14).sub.2, C(O)NHOH, C(O)NHOR.sup.14,
C(O)NHSO.sub.2R.sup.14, C(O)NR.sup.14SO.sub.2R.sup.14,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.14, SO.sub.2N(R.sup.14).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
wherein each aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is
optionally substituted with one or more independently selected
R.sup.15, OR.sup.15, SR.sup.15, S(O)R.sup.15, SO.sub.2R.sup.15,
C(O)R.sup.15, CO(O)R.sup.15, OC(O)R.sup.15, OC(O)OR.sup.15,
NH.sub.2, NHR.sup.15, N(R.sup.15).sub.2, NHC(O)R.sup.15,
NR.sup.15C(O)R.sup.15, NHS(O).sub.2R.sup.15,
NR.sup.15S(O).sub.2R.sup.15, NHC(O)OR.sup.15,
NR.sup.15C(O)OR.sup.15, NHC(O)NH.sub.2, NHC(O)NHR.sup.15,
NHC(O)N(R.sup.15).sub.2, NR.sup.15C(O)NHR.sup.15,
NR.sup.15C(O)N(R.sup.15).sub.2, C(O)NH.sub.2, C(O)NHR.sup.15,
C(O)N(R.sup.15).sub.2, C(O)NHOH, C(O)NHOR.sup.15,
C(O)NHSO.sub.2R.sup.15, C(O)NR.sup.15SO.sub.2R.sup.15,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.15, SO.sub.2N(R.sup.15).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0065] R.sup.14 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected NH.sub.2, SO.sub.2NH.sub.2, C(O)H, C(O)OH, OH, (O), CN,
N.sub.3, NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3,
OCF.sub.2CF.sub.3, F, Cl, Br or I; and
[0066] R.sup.15 is alkyl.
[0067] Another embodiment of this invention pertains to compounds
or pharmaceutically acceptable salts thereof; which are useful as
inhibitors of NAMPT, the compounds having Formula (VI)
##STR00005##
[0068] wherein
[0069] indicates a single or a double bond;
[0070] X.sup.1 and X.sup.2 and X.sup.3 are CH; or
[0071] X.sup.1 and X.sup.3 are CH; and X.sup.2 is N; or
[0072] X.sup.2 and X.sup.3 are H; and X.sup.1 is N; or
[0073] X.sup.1 is CR.sup.1; and X.sup.2 and X.sup.3 are CH; or
[0074] X.sup.2 is CR.sup.1; and X.sup.1 and X.sup.3 are CH; or
[0075] X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are CH;
[0076] R.sup.1 is R.sup.3, OR.sup.3, SR.sup.3, S(O)R.sup.3,
SO.sub.2R.sup.3C(O)R.sup.3, C(O)OR.sup.3, OC(O)R.sup.3, NHR.sup.3,
N(R.sup.3).sub.2, C(O)NH.sub.2, C(O)NHR.sup.3,
C(O)N(R.sup.3).sub.2, NHC(O)R.sup.3, NR.sup.3C(O)R.sup.3,
NHC(O)OR.sup.3, NR.sup.3C(O)OR.sup.3, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.3, SO.sub.2N(R.sup.3).sub.2, NHSO.sub.2R.sup.3,
NR.sup.3SO.sub.2R.sup.3, NHSO.sub.2NHR.sup.3,
NHSO.sub.2N(R.sup.3).sub.2, NR.sup.3SO.sub.2NHR.sup.3,
NR.sup.3SO.sub.2N(R.sup.3).sub.2, C(O)NHSO.sub.2R.sup.3,
NHSO.sub.2NHR.sup.3, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, N.sub.3,
OH, C(O)H, CF.sub.3, C(O)OH, or C(O)NH.sub.2;
[0077] R.sup.3 is alkyl, alkenyl, alkynyl, aryl, or heterocyclyl;
wherein each alkyl, alkenyl, and alkynyl is optionally substituted
with one or more independently selected R.sup.6, OR.sup.6,
SR.sup.6, S(O)R.sup.6, SO.sub.2R.sup.6, C(O)R.sup.6, CO(O)R.sup.6,
OC(O)R.sup.6, OC(O)OR.sup.6, NH.sub.2, NHR.sup.6, N(R.sup.6).sub.2,
NHC(O)R.sup.6, NR.sup.6C(O)R.sup.6, NHS(O).sub.2R.sup.6,
NR.sup.6S(O).sub.2R.sup.6, NHC(O)OR.sup.6, NR.sup.6C(O)OR.sup.6,
NHC(O)NH.sub.2, NHC(O)NHR.sup.6, NHC(O)N(R.sup.6).sub.2,
NR.sup.6C(O)NHR.sup.6, NR.sup.6C(O)N(R.sup.6).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.6, C(O)N(R.sup.6).sub.2, C(O)NHOH, C(O)NHOR.sup.6,
C(O)NHSO.sub.2R.sup.6, C(O)NR.sup.6SO.sub.2R.sup.6,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.6, SO.sub.2N(R.sup.6).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0078] R.sup.6 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10,
SO.sub.2R.sup.10, NHR.sup.10, N(R.sup.10).sub.2, C(O)R.sup.10,
C(O)NH.sub.2, C(O)NHR.sup.10, C(O)N(R.sup.10).sub.2,
NHC(O)R.sup.10, NR.sup.10C(O)R.sup.10, NHSO.sub.2R.sup.10,
NHC(O)OR.sup.10, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10,
SO.sub.2N(R.sup.10).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.10, OH,
(O), C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F,
Cl, Br or I;
[0079] R.sup.10 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl;
[0080] R.sup.y is R.sup.13, OR.sup.13, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, C(O)R.sup.13, CO(O)R.sup.13, OC(O)R.sup.13,
OC(O)OR.sup.13, NH.sub.2, NHR.sup.13, N(R.sup.13).sub.2,
NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13, NHS(O).sub.2R.sup.13,
NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0081] R.sup.13 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.14, OR.sup.14, SR.sup.14, S(O)R.sup.14,
SO.sub.2R.sup.14, C(O)R.sup.14, CO(O)R.sup.14, OC(O)R.sup.14,
OC(O)OR.sup.14, NH.sub.2, NHR.sup.14, N(R.sup.14).sub.2,
NHC(O)R.sup.14, NR.sup.14C(O)R.sup.14, NHS(O).sub.2R.sup.14,
NR.sup.14S(O).sub.2R.sup.14, NHC(O)OR.sup.14,
NR.sup.14C(O)OR.sup.14, NHC(O)NH.sub.2, NHC(O)NHR.sup.14,
NHC(O)N(R.sup.14).sub.2, NR.sup.14C(O)NHR.sup.14,
NR.sup.14C(O)N(R.sup.14).sub.2, C(O)NH.sub.2, C(O)NHR.sup.14,
C(O)N(R.sup.14).sub.2, C(O)NHOH, C(O)NHOR.sup.14,
C(O)NHSO.sub.2R.sup.14, C(O)NR.sup.14SO.sub.2R.sup.14,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.14, SO.sub.2N(R.sup.14).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
wherein each aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is
optionally substituted with one or more independently selected
R.sup.15, OR.sup.15, SR.sup.15, S(O)R.sup.15, SO.sub.2R.sup.15,
C(O)R.sup.15, CO(O)R.sup.15, OC(O)R.sup.15, OC(O)OR.sup.15,
NH.sub.2, NHR.sup.15, N(R.sup.15).sub.2, NHC(O)R.sup.15,
NR.sup.15C(O)R.sup.15, NHS(O).sub.2R.sup.15,
NR.sup.15S(O).sub.2R.sup.15, NHC(O)OR.sup.15,
NR.sup.15C(O)OR.sup.15, NHC(O)NH.sub.2, NHC(O)NHR.sup.15,
NHC(O)N(R.sup.15).sub.2, NR.sup.15C(O)NHR.sup.15,
NR.sup.15C(O)N(R.sup.15).sub.2, C(O)NH.sub.2, C(O)NHR.sup.15,
C(O)N(R.sup.15).sub.2, C(O)NHOH, C(O)NHOR.sup.15,
C(O)NHSO.sub.2R.sup.15, C(O)NR.sup.15SO.sub.2R.sup.15,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.15, SO.sub.2N(R.sup.15).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0082] R.sup.14 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected NH.sub.2, SO.sub.2NH.sub.2, C(O)H, C(O)OH, OH, (O), CN,
N.sub.3, NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3,
OCF.sub.2CF.sub.3, F, Cl, Br or I; and
[0083] R.sup.15 is alkyl.
[0084] In one embodiment of Formula (VI), is a double bond.
[0085] Another embodiment pertains to compounds of Formula (I),
(IV), (V), (VI), and pharmaceutically acceptable salts thereof;
wherein X.sup.1, X.sup.2, and X.sup.3 are CH; or X.sup.1 is
CR.sup.1 and X.sup.2 and X.sup.3 are CH; or X.sup.2 is CR.sup.1 and
X.sup.1 and X.sup.3 are CH.
[0086] Another embodiment pertains to compounds of (I), (IV), (V),
(VI), and pharmaceutically acceptable salts thereof; wherein
X.sup.1 and X.sup.3 are CH; and X.sup.2 is N; or X.sup.2 and
X.sup.3 are CH; and X.sup.1 is N.
[0087] Still another embodiment pertains to compounds, which are
[0088]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0089]
N-(4-{[4-(pyridin-2-yl)piperazin-1-yl]carbonyl}phenyl)-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0090]
6-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0091]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1-
H)-carboxamide; [0092]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1H-
)-carboxamide; [0093]
6-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0094]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0095]
N-[4-(benzylcarbamoyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0096]
N-{5-[(3-phenylpropyl)carbamoyl]pyridin-2-yl}-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0097]
N-{5-[(3-methylbutyl)carbamoyl]pyridin-2-yl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0098]
N-(4-{[1-(3-methylbutyl)-1H-pyrazol-4-yl]carbamoyl}phenyl)-3,4-dihydroiso-
quinoline-2(1H)-carboxamide; [0099]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,6-naphthyridine-
-2(1H)-carboxamide; [0100]
6-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0101]
N-{4-[(1-benzyl-1H-pyrazol-4-yl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0102]
N-{4-[(2-phenylethyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0103]
7-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0104]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0105]
N-{6-[(3-methylbutyl)carbamoyl]pyridin-3-yl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0106]
N-(5-{[2-(2-thienyl)ethyl]carbamoyl}pyridin-2-yl)-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0107]
7-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0108]
N-{6-[(3-phenylpropyl)carbamoyl]pyridin-3-yl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide; [0109]
N-(6-{[2-(2-thienyl)ethyl]carbamoyl}pyridin-3-yl)-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0110]
7-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0111]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1-
H)-carboxamide; [0112]
N-[4-(2-oxo-2-{[2-(2-thienyl)ethyl]amino}ethyl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0113]
N-(4-{2-oxo-2-[(3-phenylpropyl)amino]ethyl}phenyl)-3,4-dihydroisoquinolin-
e-2(1H)-carboxamide; [0114]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1H-
)-carboxamide; [0115]
N-(4-{2-[(3-methylbutyl)amino]-2-oxoethyl}phenyl)-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0116]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,7-naphthyridine-
-2(1H)-carboxamide; [0117]
N-{4-[(4-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0118]
N-{4-[(4-phenylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0119]
N-(4-{[3-(2-thienyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0120]
N-[4-(1-isobutyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-ca-
rboxamide; [0121]
N-[4-(1-propyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0122]
N-{4-[1-((2R)-2-hydroxypropyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0123]
N-{4-[1-(3-methylbutyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0124]
N-[4-(1-benzyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0125]
N-{4-[(1E)-5-phenylpent-1-en-1-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0126]
N-[4-(1-ethyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0127]
N-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0128]
N-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0129]
N-[4-(1-benzoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0130]
N-[4-(1-butyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0131]
N-{4-[1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-di-
hydroisoquinoline-2(1H)-carboxamide; [0132]
N-[4-(1-isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoq-
uinoline-2(1H)-carboxamide; [0133]
N-{4-[1-(3-methylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide; [0134]
N-{4-[1-(methylcarbamoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihy-
droisoquinoline-2(1H)-carboxamide; [0135] tert-butyl
4-{4-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]phenyl}-3,6-dihydrop-
yridine-1(2H)-carboxylate; [0136]
N-[4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0137]
N-{4-[1-(isobutylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide; [0138]
N-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0139]
N-{4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide; [0140]
N-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0141]
N-{4-[1-(3-methylbutyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydr-
oisoquinoline-2(1H)-carboxamide; [0142]
N-[4-(5-propyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0143]
N-[4-(5-benzyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0144]
N-{4-[5-(3-methylbutyl)-1,2,4-oxadiazol-3-yl]phenyl}-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0145]
N-hexyl-3,4-dihydroisoquinoline-2(1H)-carboxamide; [0146] ethyl
6-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]hexanoate; [0147]
N-(4-{2-[(phenylacetyl)amino]ethyl}phenyl)-3,4-dihydroisoquinoline-2(1H)--
carboxamide; [0148]
N-{4-[2-(isobutyrylamino)ethyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0149]
N-(4-{[(benzyloxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0150]
N-(4-{[(4-methoxycyclohexyl)carbonyl]amino}phenyl)-3,4-dihydroisoquinolin-
e-2(1H)-carboxamide; [0151]
N-(4-{[(1-acetylpiperidin-4-yl)carbonyl]amino}phenyl)-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0152]
N-(4-{[4-oxo-4-(2-thienyl)butanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0153]
N-(4-{[3-(phenylsulfonyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0154]
N-{4-[((2R)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide and
N-{4-[((2S)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide; [0155] N
N-{4-[((3R)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide and
N-{4-[((3S)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0156]
N-{4-[(2,2-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0157]
N-{4-[(3,3-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0158]
N-[4-(heptanoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0159]
N-{4-[(4,4,4-trifluorobutanoyl)amino]phenyl}-3,4-dihydroisoquinoli-
ne-2(1H)-carboxamide; [0160]
N-(4-{[(2-methoxyethoxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0161]
N-{4-[((3R)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide and
N-{4-[((3S)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0162]
N-(4-{[3-(methylthio)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0163]
N-{4-[(cyclopentylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0164]
N-{4-[(cyclohexylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0165]
N-{4-[(cyclohexylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0166]
N-[4-(benzoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0167]
N-{4-[(phenylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-ca-
rboxamide; [0168]
N-(4-{[3-(4-aminophenyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0169]
N-[4-(3-furoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0170]
N-{4-[(2,5-dimethyl-3-furoyl)amino]phenyl}-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0171]
N-{4-[(3-thienylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0172]
N-{4-[(1H-pyrrol-2-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0173]
N-{4-[(1,3-thiazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide; [0174]
N-{4-[(1H-pyrazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0175]
N-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0176]
N-{4-[(1,2-oxazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0177]
N-{4-[(pyridin-2-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0178]
N-{4-[(N,N-dimethyl-beta-alanyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide; [0179]
N-(4-{[3-(piperidin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0180]
N-{4-[(morpholin-4-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0181]
N-(4-{[3-(morpholin-4-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0182]
N-(4-{[3-(4-methylpiperazin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoqu-
inoline-2(1H)-carboxamide; [0183]
N-[4-(trifluoromethyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0184]
N-{4-[(cyclopentylacetyl)amino]phenyl}-5-[(methylsulfonyl)amino]-3-
,4-dihydroisoquinoline-2(1H)-carboxamide; and pharmaceutically
acceptable salts thereof.
[0185] Still another embodiment pertains to compounds of Formula
(V), which are [0186]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0187]
N-(4-{[4-(pyridin-2-yl)piperazin-1-yl]carbonyl}phenyl)-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0188]
6-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0189]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1-
H)-carboxamide; [0190]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1H-
)-carboxamide; [0191]
6-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0192]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0193]
N-[4-(benzylcarbamoyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0194]
N-(4-{[1-(3-methylbutyl)-1H-pyrazol-4-yl]carbamoyl}phenyl)-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide; [0195]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,6-naphthyridine-
-2(1H)-carboxamide; [0196]
6-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0197]
N-{4-[(1-benzyl-1H-pyrazol-4-yl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0198]
N-{4-[(2-phenylethyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0199]
7-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0200]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0201]
7-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0202]
7-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0203]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1-
H)-carboxamide; [0204]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1H-
)-carboxamide; [0205]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,7-naphthyridine-
-2(1H)-carboxamide; and pharmaceutically acceptable salts
thereof.
[0206] Still another embodiment pertains to compounds of Formula
(IV), which are [0207]
N-{4-[(4-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0208]
N-{4-[(4-phenylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0209]
N-(4-{[3-(2-thienyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0210]
N-(4-{[(benzyloxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0211]
N-(4-{[(4-methoxycyclohexyl)carbonyl]amino}phenyl)-3,4-dihydroisoquinolin-
e-2(1H)-carboxamide; [0212]
N-(4-{[(1-acetylpiperidin-4-yl)carbonyl]amino}phenyl)-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0213]
N-(4-{[4-oxo-4-(2-thienyl)butanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0214]
N-(4-{[3-(phenylsulfonyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0215]
N-{4-[((2R)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide and
N-{4-[((2S)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide; [0216] N
N-{4-[((3R)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide and
N-{4-[((3S)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0217]
N-{4-[(2,2-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0218]
N-{4-[(3,3-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0219]
N-[4-(heptanoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0220]
N-{4-[(4,4,4-trifluorobutanoyl)amino]phenyl}-3,4-dihydroisoquinoli-
ne-2(1H)-carboxamide; [0221]
N-(4-{[(2-methoxyethoxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0222]
N-{4-[((3R)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide and
N-{4-[((3S)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0223]
N-(4-{[3-(methylthio)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0224]
N-{4-[(cyclopentylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0225]
N-{4-[(cyclohexylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0226]
N-{4-[(cyclohexylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0227]
N-[4-(benzoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0228]
N-{4-[(phenylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-ca-
rboxamide; [0229]
N-(4-{[3-(4-aminophenyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0230]
N-[4-(3-furoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0231]
N-{4-[(2,5-dimethyl-3-furoyl)amino]phenyl}-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0232]
N-{4-[(3-thienylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0233]
N-{4-[(1H-pyrrol-2-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0234]
N-{4-[(1,3-thiazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide; [0235]
N-{4-[(1H-pyrazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0236]
N-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0237]
N-{4-[(1,2-oxazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0238]
N-{4-[(pyridin-2-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0239]
N-{4-[(N,N-dimethyl-beta-alanyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide; [0240]
N-(4-{[3-(piperidin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0241]
N-{4-[(morpholin-4-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0242]
N-(4-{[3-(morpholin-4-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0243]
N-(4-{[3-(4-methylpiperazin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoqu-
inoline-2(1H)-carboxamide; [0244]
N-{4-[(cyclopentylacetyl)amino]phenyl}-5-[(methylsulfonyl)amino]-3,4-dihy-
droisoquinoline-2(1H)-carboxamide; and pharmaceutically acceptable
salts thereof.
[0245] Still another embodiment pertains to compounds of Formula
(VI), which are [0246]
N-[4-(1-benzoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0247]
N-[4-(1-butyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0248]
N-{4-[1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-di-
hydroisoquinoline-2(1H)-carboxamide; [0249]
N-[4-(1-isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoq-
uinoline-2(1H)-carboxamide; [0250]
N-{4-[1-(3-methylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide; [0251]
N-{4-[1-(methylcarbamoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihy-
droisoquinoline-2(1H)-carboxamide; [0252] tert-butyl
4-{4-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]phenyl}-3,6-dihydrop-
yridine-1(2H)-carboxylate; [0253]
N-[4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0254]
N-{4-[1-(isobutylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide; [0255]
N-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0256]
N-{4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide; [0257]
N-{4-[1-(3-methylbutyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydr-
oisoquinoline-2(1H)-carboxamide; and pharmaceutically acceptable
salts thereof.
[0258] Another embodiment pertains to a composition for treating
inflammatory and tissue repair disorders; particularly rheumatoid
arthritis, inflammatory bowel disease, asthma and COPD (chronic
obstructive pulmonary disease), osteoarthritis, osteoporosis and
fibrotic diseases; dermatosis, including psoriasis, atopic
dermatitis and ultra-violet induced skin damage; autoimmune
diseases including systemic upus erythematosis, multiple sclerosis,
psoriatic arthritis, ankylosing spondylitis, tissue and organ
rejection, Alzheimer's disease, stroke, athersclerosis, restenosis,
diabetes, glomerulonephritis, cancer, particularly wherein the
cancer is selected from breast, prostate, lung, colon, cervix,
ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or
Hodgkin's disease, cachexia, inflammation associated with infection
and certain viral infections, including Acquired Immune Deficiency
Syndrome (AIDS), adult respiratory distress syndrome, and ataxia
telengiectasia, said composition comprising an excipient and a
therapeutically effective amount of a compound of Formula (I), or
pharmaceutically acceptable salts thereof.
[0259] Another embodiment pertains to a method of treating
inflammatory and tissue repair disorders; particularly rheumatoid
arthritis, inflammatory bowel disease, asthma and COPD (chronic
obstructive pulmonary disease), osteoarthritis, osteoporosis and
fibrotic diseases; dermatosis, including psoriasis, atopic
dermatitis and ultra-violet induced skin damage; autoimmune
diseases including systemic lupus erythematosis, multiple
sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and
organ rejection, Alzheimer's disease, stroke, athersclerosis,
restenosis, diabetes, glomerulonephritis, cancer, particularly
wherein the cancer is selected from breast, prostate, lung, colon,
cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or
Hodgkin's disease, cachexia, inflammation associated with infection
and certain viral infections, including Acquired Immune Deficiency
Syndrome (AIDS), adult respiratory distress syndrome, and ataxia
telengiectasia in a patient, said method comprising administering
to the patient a therapeutically effective amount of a compound of
Formula (I) or Formula (V), or pharmaceutically acceptable salts
thereof.
[0260] Another embodiment pertains to a method of treating
inflammatory and tissue repair disorders; particularly rheumatoid
arthritis, inflammatory bowel disease, asthma and COPD (chronic
obstructive pulmonary disease), osteoarthritis, osteoporosis and
fibrotic diseases; dermatosis, including psoriasis, atopic
dermatitis and ultra-violet induced skin damage; autoimmune
diseases including systemic lupus erythematosis, multiple
sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and
organ rejection, Alzheimer's disease, stroke, athersclerosis,
restenosis, diabetes, glomerulonephritis, cancer, particularly
wherein the cancer is selected from breast, prostate, lung, colon,
cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or
Hodgkin's disease, cachexia, inflammation associated with infection
and certain viral infections, including Acquired Immune Deficiency
Syndrome (AIDS), adult respiratory distress syndrome, and ataxia
telengiectasia or spleen cancer in a patient, said method
comprising administering to the patient therapeutically effective
amount of the compound of Formula (I), or pharmaceutically
acceptable salts thereof; and a therapeutically effective amount of
one additional therapeutic agent or more than one additional
therapeutic agent.
DETAILED DESCRIPTION OF THE INVENTION
[0261] This detailed description is intended only to acquaint
others skilled in the art with Applicants' invention, its
principles, and its practical application so that others skilled in
the art may adapt and apply the invention in its numerous forms, as
they may be best suited to the requirements of a particular use.
This description and its specific examples are intended for
purposes of illustration only. This invention, therefore, is not
limited to the embodiments described in this patent application,
and may be variously modified.
ABBREVIATIONS AND DEFINITIONS
[0262] Unless otherwise defined herein, scientific and technical
terms used in connection with the present invention shall have the
meanings that are commonly understood by those of ordinary skill in
the art. The meaning and scope of the terms should be clear,
however, in the event of any latent ambiguity, definitions provided
herein take precedent over any dictionary or extrinsic definition.
In this application, the use of "or" means "and/or" unless stated
otherwise. Furthermore, the use of the term "including", as well as
other forms, such as "includes" and "included", is not limiting.
With reference to the use of the words "comprise" or "comprises" or
"comprising" in this patent application (including the claims),
Applicants note that unless the context requires otherwise, those
words are used on the basis and clear understanding that they are
to be interpreted inclusively, rather than exclusively, and that
Applicants intend each of those words to be so interpreted in
construing this patent application, including the claims below. For
a variable that occurs more than one time in any substituent or in
the compound of the invention or any other formulae herein, its
definition on each occurrence is independent of its definition at
every other occurrence. Combinations of substituents are
permissible only if such combinations result in stable compounds.
Stable compounds are compounds which can be isolated in a useful
degree of purity from a reaction mixture.
[0263] It is meant to be understood that proper valences are
maintained for all combinations herein, that monovalent moieties
having more than one atom are attached through their left ends, and
that divalent moieties are drawn from left to right.
[0264] As used in the specification and the appended claims, unless
specified to the contrary, the following terms have the meaning
indicated:
[0265] The term "alkyl" (alone or in combination with another
term(s)) means a straight- or branched-chain saturated hydrocarbyl
substituent typically containing from 1 to about 10 carbon atoms;
or in another embodiment, from 1 to about 8 carbon atoms; in
another embodiment, from 1 to about 6 carbon atoms; and in another
embodiment, from 1 to about 4 carbon atoms. Examples of such
substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, and hexyl and
the like.
[0266] The term "alkenyl" (alone or in combination with another
term(s)) means a straight- or branched-chain hydrocarbyl
substituent containing one or more double bonds and typically from
2 to about 10 carbon atoms; or in another embodiment, from 2 to
about 8 carbon atoms; in another embodiment, from 2 to about 6
carbon atoms; and in another embodiment, from 2 to about 4 carbon
atoms. Examples of such substituents include ethenyl(vinyl),
2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl,
2-butenyl, and 3-butenyl and the like.
[0267] The term "alkynyl" (alone or in combination with another
term(s)) means a straight- or branched-chain hydrocarbyl
substituent containing one or more triple bonds and typically from
2 to about 10 carbon atoms; or in another embodiment, from 2 to
about 8 carbon atoms; in another embodiment, from 2 to about 6
carbon atoms; and in another embodiment, from 2 to about 4 carbon
atoms. Examples of such substituents include ethynyl, 2-propynyl,
3-propynyl, 2-butynyl, and 3-butynyl and the like.
[0268] The term "carbocyclyl" (alone or in combination with another
term(s)) means a saturated cyclic (i.e., "cycloalkyl"), partially
saturated cyclic (i.e., "cycloalkenyl"), or completely unsaturated
(i.e., "aryl") hydrocarbyl substituent containing from 3 to 14
carbon ring atoms ("ring atoms" are the atoms bound together to
form the ring or rings of a cyclic substituent). A carbocyclyl may
be a single-ring (monocyclic) or polycyclic ring structure.
[0269] A carbocyclyl may be a single ring structure, which
typically contains from 3 to 8 ring atoms, more typically from 3 to
6 ring atoms, and even more typically 5 to 6 ring atoms. Examples
of such single-ring carbocyclyls include cyclopropyl
(cyclopropanyl), cyclobutyl (cyclobutanyl), cyclopentyl
(cyclopentanyl), cyclopentenyl, cyclopentadienyl, cyclohexyl
(cyclohexanyl), cyclohexenyl, cyclohexadienyl, and phenyl. A
carbocyclyl may alternatively be polycyclic (i.e., may contain more
than one ring). Examples of polycyclic carbocyclyls include
bridged, fused, and spirocyclic carbocyclyls. In a spirocyclic
carbocyclyl, one atom is common to two different rings. An example
of a spirocyclic carbocyclyl is spiropentanyl. In a bridged
carbocyclyl, the rings share at least two common non-adjacent
atoms. Examples of bridged carbocyclyls include
bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, and adamantanyl.
In a fused-ring carbocyclyl system, two or more rings may be fused
together, such that two rings share one common bond. Examples of
two- or three-fused ring carbocyclyls include naphthalenyl,
tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl
(dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.
[0270] The term "cycloalkyl" (alone or in combination with another
term(s)) means a saturated cyclic hydrocarbyl substituent
containing from 3 to 14 carbon ring atoms. A cycloalkyl may be a
single carbon ring, which typically contains from 3 to 8 carbon
ring atoms and more typically from 3 to 6 ring atoms. Examples of
single-ring cycloalkyls include cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl. A cycloalkyl may alternatively be
polycyclic or contain more than one ring. Examples of polycyclic
cycloalkyls include bridged, fused, and spirocyclic
carbocyclyls.
[0271] The term "aryl" (alone or in combination with another
term(s)) means an aromatic carbocyclyl containing from 6 to 14
carbon ring atoms. An aryl may be monocyclic or polycyclic (i.e.,
may contain more than one ring). In the case of polycyclic aromatic
rings, only one ring the polycyclic system is required to be
unsaturated while the remaining ring(s) may be saturated, partially
saturated or unsaturated. Examples of aryls include phenyl,
naphthalenyl, indenyl, indanyl, and tetrahydronapthyl.
[0272] In some instances, the number of carbon atoms in a
hydrocarbyl substituent (e.g., alkyl, alkenyl, alkynyl, or
cycloalkyl) is indicated by the prefix "C.sub.x-C.sub.y-", wherein
x is the minimum and y is the maximum number of carbon atoms in the
substituent. Thus, for example, "C.sub.1-C.sub.6-alkyl" refers to
an alkyl substituent containing from 1 to 6 carbon atoms.
Illustrating further, C.sub.3-C.sub.8-cycloalkyl means a saturated
hydrocarbyl ring containing from 3 to 8 carbon ring atoms.
[0273] The term "hydrogen" (alone or in combination with another
term(s)) means a hydrogen radical, and may be depicted as --H.
[0274] The term "hydroxy" (alone or in combination with another
term(s)) means --OH.
[0275] The term "carboxy" (alone or in combination with another
term(s)) means --C(O)--OH.
[0276] The term "amino" (alone or in combination with another
term(s)) means --NH.sub.2.
[0277] The term "halogen" or "halo" (alone or in combination with
another term(s)) means a fluorine radical (which may be depicted as
--F), chlorine radical (which may be depicted as --Cl), bromine
radical (which may be depicted as --Br), or iodine radical (which
may be depicted as --I).
[0278] If a substituent is described as being "substituted", a
non-hydrogen radical is in the place of hydrogen radical on a
carbon or nitrogen of the substituent. Thus, for example, a
substituted alkyl substituent is an alkyl substituent in which at
least one non-hydrogen radical is in the place of a hydrogen
radical on the alkyl substituent. To illustrate, monofluoroalkyl is
alkyl substituted with a fluoro radical, and difluoroalkyl is alkyl
substituted with two fluoro radicals. It should be recognized that
if there are more than one substitution on a substituent, each
non-hydrogen radical may be identical or different (unless
otherwise stated).
[0279] If a substituent is described as being "optionally
substituted", the substituent may be either (1) not substituted or
(2) substituted. If a substituent is described as being optionally
substituted with up to a particular number of non-hydrogen
radicals, that substituent may be either (1) not substituted; or
(2) substituted by up to that particular number of non-hydrogen
radicals or by up to the maximum number of substitutable positions
on the substituent, whichever is less. Thus, for example, if a
substituent is described as a heteroaryl optionally substituted
with up to 3 non-hydrogen radicals, then any heteroaryl with less
than 3 substitutable positions would be optionally substituted by
up to only as many non-hydrogen radicals as the heteroaryl has
substitutable positions. To illustrate, tetrazolyl (which has only
one substitutable position) would be optionally substituted with up
to one non-hydrogen radical. To illustrate further, if an amino
nitrogen is described as being optionally substituted with up to 2
non-hydrogen radicals, then a primary amino nitrogen will be
optionally substituted with up to 2 non-hydrogen radicals, whereas
a secondary amino nitrogen will be optionally substituted with up
to only 1 non-hydrogen radical.
[0280] This patent application uses the terms "substituent" and
"radical" interchangeably. The prefix "halo" indicates that the
substituent to which the prefix is attached is substituted with one
or more independently selected halogen radicals. For example,
haloalkyl means an alkyl substituent in which at least one hydrogen
radical is replaced with a halogen radical. Examples of haloalkyls
include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, and 1,1,1-trifluoroethyl. It should be recognized
that if a substituent is substituted by more than one halogen
radical, those halogen radicals may be identical or different
(unless otherwise stated).
[0281] The prefix "perhalo" indicates that every hydrogen radical
on the substituent to which the prefix is attached is replaced with
independently selected halogen radicals, i.e., each hydrogen
radical on the substituent is replaced with a halogen radical. If
all the halogen radicals are identical, the prefix typically will
identify the halogen radical. Thus, for example, the term
"perfluoro" means that every hydrogen radical on the substituent to
which the prefix is attached is substituted with a fluorine
radical. To illustrate, the term "perfluoroalkyl" means an alkyl
substituent wherein a fluorine radical is in the place of each
hydrogen radical.
[0282] The term "carbonyl" (alone or in combination with another
term(s)) means --C(O)--. The term "aminocarbonyl" (alone or in
combination with another term(s)) means --C(O)--NH.sub.2.
[0283] The term "oxo" (alone or in combination with another
term(s)) means (.dbd.O).
[0284] The term "oxy" (alone or in combination with another
term(s)) means an ether substituent, and may be depicted as
--O--.
[0285] The term "alkylhydroxy" (alone or in combination with
another term(s)) means -alkyl-OH.
[0286] The term "alkylamino" (alone or in combination with another
term(s)) means -alkyl-NH.sub.2.
[0287] The term "alkyloxy" (alone or in combination with another
term(s)) means an alkylether substituent, i.e., --O-alkyl. Examples
of such a substituent include methoxy (--O--CH.sub.3), ethoxy,
n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and
tert-butoxy.
[0288] The term "alkylcarbonyl" (alone or in combination with
another term(s)) means --C(O)-alkyl.
[0289] The term "aminoalkylcarbonyl" (alone or in combination with
another term(s)) means --C(O)-alkyl-NH.sub.2.
[0290] The term "alkyloxycarbonyl" (alone or in combination with
another term(s)) means --C(O)--O-alkyl.
[0291] The term "carbocyclylcarbonyl" (alone or in combination with
another term(s)) means --C(O)-carbocyclyl.
[0292] Similarly, the term "heterocyclylcarbonyl" (alone or in
combination with another term(s)) means --C(O)-heterocyclyl.
[0293] The term "carbocyclylalkylcarbonyl" (alone or in combination
with another term(s)) means --C(O)-alkyl-carbocyclyl.
[0294] Similarly, the term "heterocyclylalkylcarbonyl" (alone or in
combination with another term(s)) means
--C(O)-alkyl-heterocyclyl.
[0295] The term "carbocyclyloxycarbonyl" (alone or in combination
with another term(s)) means --C(O)--O-carbocyclyl.
[0296] The term "carbocyclylalkyloxycarbonyl" (alone or in
combination with another term(s)) means
--C(O)--O-alkyl-carbocyclyl.
[0297] The term "thio" or "thia" (alone or in combination with
another term(s)) means a thiaether substituent, i.e., an ether
substituent wherein a divalent sulfur atom is in the place of the
ether oxygen atom. Such a substituent may be depicted as --S--.
This, for example, "alkyl-thio-alkyl" means alkyl-S-alkyl
(alkyl-sulfanyl-alkyl).
[0298] The term "thiol" or "sulfhydryl" (alone or in combination
with another term(s)) means a sulfhydryl substituent, and may be
depicted as --SH.
The term "(thiocarbonyl)" (alone or in combination with another
term(s)) means a carbonyl wherein the oxygen atom has been replaced
with a sulfur. Such a substituent may be depicted as --C(S)--.
[0299] The term "sulfonyl" (alone or in combination with another
term(s)) means --S(O).sub.2--.
[0300] The term "aminosulfonyl" (alone or in combination with
another term(s)) means --S(O).sub.2--NH.sub.2.
[0301] The term "sulfinyl" or "sulfoxido" (alone or in combination
with another term(s)) means --S(O)--.
[0302] The term "heterocyclyl" (alone or in combination with
another term(s)) means a saturated (i.e., "heterocycloalkyl"),
partially saturated (i.e., "heterocycloalkenyl"), or completely
unsaturated (i.e., "heteroaryl") ring structure containing a total
of 3 to 14 ring atoms. At least one of the ring atoms is a
heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining
ring atoms being independently selected from the group consisting
of carbon, oxygen, nitrogen, and sulfur. A heterocyclyl may be a
single-ring (monocyclic) or polycyclic ring structure.
[0303] A heterocyclyl may be a single ring, which typically
contains from 3 to 7 ring atoms, more typically from 3 to 6 ring
atoms, and even more typically 5 to 6 ring atoms. Examples of
single-ring heterocyclyls include 1,2,3,6-tetrahydropyridine,
thiomorpholinyl, tetrahydropyranyl, furanyl, dihydrofuranyl,
tetrahydrofuranyl, thiophenyl (thiofuranyl), dihydrothiophenyl,
tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl,
imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl,
pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl, oxazolidinyl,
isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl,
isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl,
oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,5-oxadiazolyl(furazanyl), or 1,3,4-oxadiazolyl), oxatriazolyl
(including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl),
dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl,
1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl,
oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl,
tetrahydrothiopyranyl, pyridinyl(azinyl), piperidinyl, diazinyl
(including pyridazinyl (1,2-diazinyl), pyrimidinyl(1,3-diazinyl),
or pyrazinyl(1,4-diazinyl)), piperazinyl, pyrrolidin-2-only,
triazinyl (including 1,3,5-triazinyl, 1,2,4-triazinyl, and
1,2,3-triazinyl)), oxazinyl (including 1,2-oxazinyl, 1,3-oxazinyl,
or 1,4-oxazinyl)), oxathiazinyl (including 1,2,3-oxathiazinyl,
1,2,4-oxathiazinyl, 1,2,5-oxathiazinyl, or 1,2,6-oxathiazinyl)),
oxadiazinyl (including 1,2,3-oxadiazinyl, 1,2,4-oxadiazinyl,
1,4,2-oxadiazinyl, or 1,3,5-oxadiazinyl)), morpholinyl, azepinyl,
oxepinyl, thiepinyl, and diazepinyl.
[0304] A heterocyclyl may alternatively be polycyclic (i.e., may
contain more than one ring). Examples of polycyclic heterocyclyls
include bridged, fused, and spirocyclic heterocyclyls. In a
spirocyclic heterocyclyl, one atom is common to two different
rings. In a bridged heterocyclyl, the rings share at least two
common non-adjacent atoms. In a fused-ring heterocyclyl, two or
more rings may be fused together, such that two rings share one
common bond. Examples of fused-ring heterocyclyls include
hexahydro-furo[3,4-c]pyrrole, hexahydro-furo[3,4-b]pyrrole,
octahydro-pyrrolo[3,4-b]pyridine, octahydro-pyrrolo[3,4-c]pyridine,
(3aR,6aR)-5-methyl-octahydro-pyrrolo[3,4-b]pyrrole,
(3aR,6aR)-octahydro-pyrrolo[3,4-b]pyrrole,
6-methyl-2,6-diaza-bicyclo[3.2.0]heptane,
(3aS,6aR)-2-methyl-octahydro-pyrrolo[3,4-c]pyrrole,
decahydro-[1,5]naphthyridine, 2,3-dihydrobenzofuranyl,
2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indolyl, thieno[3,2-c]pyridinyl,
furo[3,2-c]pyridinyl, phthalazin-1(2H)-onyl, isoquinolinyl,
isoquinolin-1(2H)-onyl, 5,6,7,8-tetrahydrophthalazin-1(2H)-onyl,
fluorophthalazin-1(2H)-onyl,
(Z)-3H-benzo[d][1,2]diazepin-4(5H)-onyl,
(trifluoromethyl)phthalazin-1(2H)-onyl,
pyrrolo[1,2-d][1,2,4]triazin-1(2H)-onyl,
1,2,3,4-tetrahydroisoquinolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl,
5,6,7,8-tetrahydrophthalazin-1(2H)-onyl,
5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,
5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl, thieno[3,2-c]pyridinyl,
furo[3,2-c]pyridinyl, indolizinyl, pyranopyrrolyl, 4H-quinolizinyl,
purinyl, naphthyridinyl, pyridopyridinyl (including
pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or
pyrido[4,3-b]-pyridinyl), and pteridinyl. Other examples of
fused-ring heterocyclyls include benzo-fused heterocyclyls, such as
benzimidazolyl, benzo[d][1,3]dioxolyl, indolyl, isoindolyl
(isobenzazolyl, pseudoisoindolyl), indoleninyl (pseudoindolyl),
isoindazolyl (benzpyrazolyl), benzazinyl (including quinolinyl
(1-benzazinyl) or isoquinolinyl (2-benzazinyl)), phthalazinyl,
quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl
(1,2-benzodiazinyl) or quinazolinyl (1,3-benzodiazinyl)),
benzopyranyl (including chromanyl or isochromanyl), benzoxazinyl
(including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl,
2,3,1-benzoxazinyl, or 3,1,4-benzoxazinyl), and benzisoxazinyl
(including 1,2-benzisoxazinyl or 1,4-benzisoxazinyl). Examples of
spirocyclic heterocyclyls include
1,4-dioxa-8-azaspiro[4.5]decanyl.
[0305] The term "heterocycloalkyl" (alone or in combination with
another term(s)) means a saturated heterocyclyl.
[0306] The term "heteroaryl" (alone or in combination with another
term(s)) means an aromatic heterocyclyl containing from 5 to 14
ring atoms. A heteroaryl may be a single ring or 2 or 3 fused
rings. Examples of heteroaryl substituents include 6-membered ring
substituents such as pyridyl, pyrazyl, pyrimidinyl, pyridazinyl,
and 1,3,5-, 1,2,4- or 1,2,3-triazinyl; 5-membered ring substituents
such as imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl,
isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl
and isothiazolyl; 6/5-membered fused ring substituents such as
benzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and
anthranilyl; and 6/6-membered fused rings such as benzopyranyl,
quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and
benzoxazinyl.
[0307] A prefix attached to a multi-component substituent only
applies to the first component. To illustrate, the term
"alkylcycloalkyl" contains two components: alkyl and cycloalkyl.
Thus, the C.sub.1-C.sub.6- prefix on
C.sub.1-C.sub.6-alkylcycloalkyl means that the alkyl component of
the alkylcycloalkyl contains from 1 to 6 carbon atoms; the
C.sub.1-C.sub.6-prefix does not describe the cycloalkyl component.
To illustrate further, the prefix "halo" on haloalkyloxyalkyl
indicates that only the alkyloxy component of the alkyloxyalkyl
substituent is substituted with one or more halogen radicals. If
halogen substitution may alternatively or additionally occur on the
alkyl component, the substituent would instead be described as
"halogen-substituted alkyloxyalkyl" rather than
"haloalkyloxyalkyl." And finally, if the halogen substitution may
only occur on the alkyl component, the substituent would instead be
described as "alkyloxyhaloalkyl."
[0308] The terms "treat", "treating" and "treatment" refer to a
method of alleviating or abrogating a disease and/or its attendant
symptoms.
[0309] The terms "prevent", "preventing" and "prevention" refer to
a method of preventing the onset of a disease and/or its attendant
symptoms or barring a subject from acquiring a disease. As used
herein, "prevent", "preventing" and "prevention" also include
delaying the onset of a disease and/or its attendant symptoms and
reducing a subject's risk of acquiring a disease.
[0310] The term "therapeutically effective amount" refers to that
amount of the compound being administered sufficient to prevent
development of or alleviate to some extent one or more of the
symptoms of the condition or disorder being treated.
[0311] The term "modulate" refers to the ability of a compound to
increase or decrease the function, or activity, of a kinase.
"Modulation", as used herein in its various forms, is intended to
encompass antagonism, agonism, partial antagonism and/or partial
agonism of the activity associated with kinase. Kinase inhibitors
are compounds that, e.g., bind to, partially or totally block
stimulation, decrease, prevent, delay activation, inactivate,
desensitize, or down regulate signal transduction. Kinase
activators are compounds that, e.g., bind to, stimulate, increase,
open, activate, facilitate, enhance activation, sensitize or up
regulate signal transduction.
[0312] The term "composition" as used herein is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts. By "pharmaceutically acceptable" it is meant the
carrier, diluent or excipient must be compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof.
[0313] The "subject" is defined herein to include animals such as
mammals, including, but not limited to, primates (e.g., humans),
cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the
like. In preferred embodiments, the subject is a human.
Isotope Enriched or Labeled Compounds
[0314] Compounds of the invention can exist in isotope-labeled or
-enriched form containing one or more atoms having an atomic mass
or mass number different from the atomic mass or mass number most
abundantly found in nature. Isotopes can be radioactive or
non-radioactive isotopes. Isotopes of atoms such as hydrogen,
carbon, phosphorous, sulfur, fluorine, chlorine, and iodine
include, but are not limited to .sup.2H, .sup.3H, .sup.13C,
.sup.14C, .sup.15N, .sup.18O, .sup.32P, .sup.35S, .sup.18F,
.sup.36Cl and .sup.125I. Compounds that contain other isotopes of
these and/or other atoms are within the scope of this
invention.
[0315] In another embodiment, the isotope-labeled compounds contain
deuterium (.sup.2H), tritium (.sup.3H) or .sup.14C isotopes.
Isotope-labeled compounds of this invention can be prepared by the
general methods well known to persons having ordinary skill in the
art. Such isotope-labeled compounds can be conveniently prepared by
carrying out the procedures disclosed in the Examples disclosed
herein and Schemes by substituting a readily available
isotope-labeled reagent for a non-labeled reagent. In some
instances, compounds may be treated with isotope-labeled reagents
to exchange a normal atom with its isotope, for example, hydrogen
for deuterium can be exchanged by the action of a deuteric acid
such as D.sub.2SO.sub.4/D.sub.2O. In addition to the above,
relevant procedures and intermediates are disclosed, for instance,
in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996); Brickner, S J
et al., J Med Chem, 39(3), 673 (1996); Mallesham, B et al., Org
Lett, 5(7), 963 (2003); PCT publications WO1997010223,
WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189;
7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013;
and US Patent Application Publication Nos. 20090137457;
20090131485; 20090131363; 20090118238; 20090111840; 20090105338;
20090105307; 20090105147; 20090093422; 20090088416; and
20090082471, the methods are hereby incorporated by reference.
[0316] The isotope-labeled compounds of the invention may be used
as standards to determine the effectiveness of Bcl-2 inhibitors in
binding assays. Isotope containing compounds have been used in
pharmaceutical research to investigate the in vivo metabolic fate
of the compounds by evaluation of the mechanism of action and
metabolic pathway of the nonisotope-labeled parent compound (Blake
et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic
studies are important in the design of safe, effective therapeutic
drugs, either because the in vivo active compound administered to
the patient or because the metabolites produced from the parent
compound prove to be toxic or carcinogenic (Foster et al., Advances
in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985;
Kato et al., J. Labelled Comp. Radiopharmaceut., 36(10):927-932
(1995); Kushner et al., Can. J. Physiol. Pharmacol., 77, 79-88
(1999).
[0317] In addition, non-radio active isotope containing drugs, such
as deuterated drugs called "heavy drugs," can be used for the
treatment of diseases and conditions related to Bcl-2 activity.
Increasing the amount of an isotope present in a compound above its
natural abundance is called enrichment. Examples of the amount of
enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79,
84, 88, 92, 96, to about 100 mol %. Replacement of up to about 15%
of normal atom with a heavy isotope has been effected and
maintained for a period of days to weeks in mammals, including
rodents and dogs, with minimal observed adverse effects (Czajka D M
and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F,
Ann. New York Acad. Sci. 1960 84: 736; Czakja D M et al., Am. J.
Physiol. 1961 201: 357). Acute replacement of as high as 15%-23% in
human fluids with deuterium was found not to cause toxicity
(Blagojevic N et al. in "Dosimetry & Treatment Planning for
Neutron Capture Therapy", Zamenhof R, Solares G and Harling O Eds.
1994. Advanced Medical Publishing, Madison Wis. pp. 125-134;
Diabetes Metab. 23: 251 (1997)).
[0318] Stable isotope labeling of a drug can alter its
physico-chemical properties such as pKa and lipid solubility. These
effects and alterations can affect the pharmacodynamic response of
the drug molecule if the isotopic substitution affects a region
involved in a ligand-receptor interaction. While some of the
physical properties of a stable isotope-labeled molecule are
different from those of the unlabeled one, the chemical and
biological properties are the same, with one important exception:
because of the increased mass of the heavy isotope, any bond
involving the heavy isotope and another atom will be stronger than
the same bond between the light isotope and that atom. Accordingly,
the incorporation of an isotope at a site of metabolism or
enzymatic transformation will slow said reactions potentially
altering the pharmacokinetic profile or efficacy relative to the
non-isotopic compound.
Compounds
[0319] Suitable groups for X.sup.1, X.sup.2, and R.sup.2 in
compounds of Formula (I) are independently selected. The described
embodiments of the present invention may be combined. Such
combination is contemplated and within the scope of the present
invention. For example, it is contemplated that embodiments for any
of X.sup.1, X.sup.2, and R.sup.2 can be combined with embodiments
defined for any other of X.sup.1, X.sup.2, and R.sup.2.
Embodiments of Formula (I)
[0320] One embodiment of this invention, therefore, pertains to
compounds or pharmaceutically acceptable salts thereof, which are
useful as inhibitors of NAMPT, the compounds having Formula (I)
##STR00006##
[0321] wherein
[0322] X.sup.1 and X.sup.2 and X.sup.3 are CH; or
[0323] X.sup.1 and X.sup.3 are CH; and X.sup.2 is N; or
[0324] X.sup.2 and X.sup.3 are H; and X.sup.1 is N; or
[0325] X.sup.1 is CR.sup.1; and X.sup.2 and X.sup.3 are CH; or
[0326] X.sup.2 is CR.sup.1; and X.sup.1 and X.sup.3 are CH; or
[0327] X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are CH;
[0328] R.sup.1 is R.sup.3, OR.sup.3, SR.sup.3, S(O)R.sup.3,
SO.sub.2R.sup.3, C(O)R.sup.3, C(O)OR.sup.3, OC(O)R.sup.3,
NHR.sup.3, N(R.sup.3).sub.2, C(O)NH.sub.2, C(O)NHR.sup.3,
C(O)N(R.sup.3).sub.2, NHC(O)R.sup.3, NR.sup.3C(O)R.sup.3,
NHC(O)OR.sup.3, NR.sup.3C(O)OR.sup.3, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.3, SO.sub.2N(R.sup.3).sub.2, NHSO.sub.2R.sup.3,
NR.sup.3SO.sub.2R.sup.3, NHSO.sub.2NHR.sup.3,
NHSO.sub.2N(R.sup.3).sub.2, NR.sup.3SO.sub.2NHR.sup.3,
NR.sup.3SO.sub.2N(R.sup.3).sub.2, C(O)NHSO.sub.2R.sup.3,
NHSO.sub.2NHR.sup.3, F, Cl, Br, I, CN, NH.sub.2, NO.sub.2, N.sub.3,
OH, C(O)H, CF.sub.3, C(O)OH, or C(O)NH.sub.2;
[0329] R.sup.2 is alkyl, alkenyl, alkynyl, phenyl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.4, OR.sup.4, SR.sup.4, S(O)R.sup.4, SO.sub.2R.sup.4,
C(O)R.sup.4, CO(O)R.sup.4, OC(O)R.sup.4, OC(O)OR.sup.4, NH.sub.2,
NHR.sup.4, N(R.sup.4).sub.2, NHC(O)R.sup.4, NR.sup.4C(O)R.sup.4,
NHS(O).sub.2R.sup.4, NR.sup.4S(O).sub.2R.sup.4, NHC(O)OR.sup.4,
NR.sup.4C(O)OR.sup.4, NHC(O)NH.sub.2, NHC(O)NHR.sup.4,
NHC(O)N(R.sup.4).sub.2, NR.sup.4C(O)NHR.sup.4,
NR.sup.4C(O)N(R.sup.4).sub.2, C(O)NH.sub.2, C(O)NHR.sup.4,
C(O)N(R.sup.4).sub.2, C(O)NHOH, C(O)NHOR.sup.4,
C(O)NHSO.sub.2R.sup.4, C(O)NR.sup.4SO.sub.2R.sup.4,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.4, SO.sub.2N(R.sup.4).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
wherein each phenyl is optionally additionally substituted at the
para position with one independently selected R.sup.5,
OCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3, SR.sup.5,
S(O)R.sup.5, SO.sub.2R.sup.5, C(O)R.sup.5, CO(O)R.sup.5,
OC(O)R.sup.5, OC(O)OR.sup.5, NH.sub.2, NHR.sup.5, N(R.sup.5).sub.2,
NHC(O)R.sup.5, NR.sup.5C(O)R.sup.5, NHS(O).sub.2R.sup.5,
NR.sup.5S(O).sub.2R.sup.5, NHC(O)OR.sup.5, NR.sup.5C(O)OR.sup.5,
NHC(O)NH.sub.2, NHC(O)NHR.sup.5, NHC(O)N(R.sup.5).sub.2,
NR.sup.5C(O)NHR.sup.5, NR.sup.5C(O)N(R.sup.5).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.5, C(O)N(R.sup.5).sub.2, C(O)NHOH, C(O)NHOR.sup.5,
C(O)NHSO.sub.2R.sup.5, C(O)NR.sup.5SO.sub.2R.sup.5,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.5, SO.sub.2N(R.sup.5).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, Br or I; wherein
each phenyl is optionally additionally substituted with one F;
wherein each heterocyclyl, cycloalkyl, and cycloalkenyl is
optionally substituted with one or more independently selected
R.sup.5, OR.sup.5, SR.sup.5, S(O)R.sup.5, SO.sub.2R.sup.5,
C(O)R.sup.5, CO(O)R.sup.5, OC(O)R.sup.5, OC(O)OR.sup.5, NH.sub.2,
NHR.sup.5, N(R.sup.5).sub.2, NHC(O)R.sup.5, NR.sup.5C(O)R.sup.5,
NHS(O).sub.2R.sup.5, NR.sup.5S(O).sub.2R.sup.5, NHC(O)OR.sup.5,
NR.sup.5C(O)OR.sup.5, NHC(O)NH.sub.2, NHC(O)NHR.sup.5,
NHC(O)N(R.sup.5).sub.2, NR.sup.5C(O)NHR.sup.5,
NR.sup.5C(O)N(R.sup.5).sub.2, C(O)NH.sub.2, C(O)NHR.sup.5,
C(O)N(R.sup.5).sub.2, C(O)NHOH, C(O)NHOR.sup.5,
C(O)NHSO.sub.2R.sup.5, C(O)NR.sup.5SO.sub.2R.sup.5,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.5, SO.sub.2N(R.sup.5).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, CF.sub.3, CF.sub.2CF.sub.3,
OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I; wherein R.sup.2 is
not 4-methylphenyl;
[0330] R.sup.3 is alkyl, alkenyl, alkynyl, aryl, or heterocyclyl;
wherein each alkyl, alkenyl, and alkynyl is optionally substituted
with one or more independently selected R.sup.6, OR.sup.6,
SR.sup.6, S(O)R.sup.6, SO.sub.2R.sup.6, C(O)R.sup.6, CO(O)R.sup.6,
OC(O)R.sup.6, OC(O)OR.sup.6, NH.sub.2, NHR.sup.6, N(R.sup.6).sub.2,
NHC(O)R.sup.6, NR.sup.6C(O)R.sup.6, NHS(O).sub.2R.sup.6,
NR.sup.6S(O).sub.2R.sup.6, NHC(O)OR.sup.6, NR.sup.6C(O)OR.sup.6,
NHC(O)NH.sub.2, NHC(O)NHR.sup.6, NHC(O)N(R.sup.6).sub.2,
NR.sup.6C(O)NHR.sup.6, NR.sup.6C(O)N(R.sup.6).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.6, C(O)N(R.sup.6).sub.2, C(O)NHOH, C(O)NHOR.sup.6,
C(O)NHSO.sub.2R.sup.6, C(O)NR.sup.6SO.sub.2R.sup.6,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.6, SO.sub.2N(R.sup.6).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0331] R.sup.4 is alkyl, alkenyl, alkynyl, aryl or heterocyclyl;
wherein each alkyl, alkenyl, and alkynyl is optionally substituted
with one or more independently selected R.sup.7, OR.sup.7,
SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7, C(O)R.sup.7, CO(O)R.sup.7,
OC(O)R.sup.7, OC(O)OR.sup.7, NH.sub.2, NHR.sup.7, N(R.sup.7).sub.2,
NHC(O)R.sup.7, NR.sup.7C(O)R.sup.7, NHS(O).sub.2R.sup.7,
NR.sup.7S(O).sub.2R.sup.7, NHC(O)OR.sup.7, NR.sup.7C(O)OR.sup.7,
NHC(O)NH.sub.2, NHC(O)NHR.sup.7, NHC(O)N(R.sup.7).sub.2,
NR.sup.7C(O)NHR.sup.7, NR.sup.7C(O)N(R.sup.7).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.7, C(O)N(R.sup.7).sub.2, C(O)NHOH, C(O)NHOR.sup.7,
C(O)NHSO.sub.2R.sup.7, C(O)NR.sup.7SO.sub.2R.sup.7,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
wherein each aryl and heterocycyl is optionally substituted with
one or more independently selected R.sup.8, OR.sup.8, SR.sup.8,
S(O)R.sup.8, SO.sub.2R.sup.8, C(O)R.sup.8, CO(O)R.sup.8,
OC(O)R.sup.8, OC(O)OR.sup.8, NH.sub.2, NHR.sup.8, N(R.sup.8).sub.2,
NHC(O)R.sup.8, NR.sup.8C(O)R.sup.8, NHS(O).sub.2R.sup.8,
NR.sup.8S(O).sub.2R.sup.8, NHC(O)OR.sup.8, NR.sup.8C(O)OR.sup.8,
NHC(O)NH.sub.2, NHC(O)NHR.sup.8, NHC(O)N(R.sup.8).sub.2,
NR.sup.8C(O)NHR.sup.8, NR.sup.8C(O)N(R.sup.8).sub.2, C(O)NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)NHOH, C(O)NHOR.sup.8,
C(O)NHSO.sub.2R.sup.8, C(O)NR.sup.8SO.sub.2R.sup.8,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.8, SO.sub.2N(R.sup.8).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0332] R.sup.5 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.9, OR.sup.9, SR.sup.9, S(O)R.sup.9, SO.sub.2R.sup.9,
C(O)R.sup.9, CO(O)R.sup.9, OC(O)R.sup.9, OC(O)OR.sup.9, NH.sub.2,
NHR.sup.9, N(R.sup.9).sub.2, NHC(O)R.sup.9, NR.sup.9C(O)R.sup.9,
NHS(O).sub.2R.sup.9, NR.sup.9S(O).sub.2R.sup.9, NHC(O)OR.sup.9,
NR.sup.9C(O)OR.sup.9, NHC(O)NH.sub.2, NHC(O)NHR.sup.9,
NHC(O)N(R.sup.9).sub.2, NR.sup.9C(O)NHR.sup.9,
NR.sup.9C(O)N(R.sup.9).sub.2, C(O)NH.sub.2, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, C(O)NHOH, C(O)NHOR.sup.9,
C(O)NHSO.sub.2R.sup.9, C(O)NR.sup.9SO.sub.2R.sup.9,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.9, SO.sub.2N(R.sup.9).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0333] R.sup.6 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.10, OR.sup.10, SR.sup.10, S(O)R.sup.10,
SO.sub.2R.sup.10, NHR.sup.10, N(R.sup.10).sub.2, C(O)R.sup.10,
C(O)NH.sub.2, C(O)NHR.sup.10, C(O)N(R.sup.10).sub.2,
NHC(O)R.sup.10, NR.sup.10C(O)R.sup.10, NHSO.sub.2R.sup.10,
NHC(O)OR.sup.10, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.10,
SO.sub.2N(R.sup.10).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.10, OH,
(O), C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F,
Cl, Br or I;
[0334] R.sup.7 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.11, OR.sup.11, SR.sup.11, S(O)R.sup.11,
SO.sub.2R.sup.11, NHR.sup.11, N(R.sup.11).sub.2, C(O)R.sup.11,
C(O)NH.sub.2, C(O)NHR.sup.11, C(O)N(R.sup.11).sub.2,
NHC(O)R.sup.11, NR.sup.11C(O)R.sup.11, NHSO.sub.2R.sup.11,
NHC(O)OR.sup.11, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.11,
SO.sub.2N(R.sup.11).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.11, OH,
(O), C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F,
Cl, Br or I;
[0335] R.sup.8 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.12, OR.sup.12, SR.sup.12, S(O)R.sup.12,
SO.sub.2R.sup.12, NHR.sup.12, N(R.sup.12).sub.2, C(O)R.sup.12,
C(O)NH.sub.2, C(O)NHR.sup.12, C(O)N(R.sup.12).sub.2,
NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12, NHSO.sub.2R.sup.12,
NHC(O)OR.sup.12, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12,
SO.sub.2N(R.sup.12).sub.2, NHC(O)NH.sub.2, NHC(O)NHR.sup.12, OH,
(O), C(O)OH, N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F,
Cl, Br or I;
[0336] R.sup.9 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected OCH.sub.3, aryl, or heterocyclyl;
[0337] R.sup.10 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl;
[0338] R.sup.11 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl;
[0339] R.sup.12 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl;
[0340] wherein the cyclic moieties represented by R.sup.3, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, and
R.sup.12 are optionally substituted with one or more independently
selected R.sup.13, OR.sup.13, SR.sup.13, S(O)R.sup.13,
SO.sub.2R.sup.13, C(O)R.sup.13, CO(O)R.sup.13, OC(O)R.sup.13,
OC(O)OR.sup.13, NH.sub.2, NHR.sup.13, N(R.sup.13).sub.2,
NHC(O)R.sup.13, NR.sup.13C(O)R.sup.13, NHS(O).sub.2R.sup.13,
NR.sup.13S(O).sub.2R.sup.13, NHC(O)OR.sup.13,
NR.sup.13C(O)OR.sup.13, NHC(O)NH.sub.2, NHC(O)NHR.sup.13,
NHC(O)N(R.sup.13).sub.2, NR.sup.13C(O)NHR.sup.13,
NR.sup.13C(O)N(R.sup.13).sub.2, C(O)NH.sub.2, C(O)NHR.sup.13,
C(O)N(R.sup.13).sub.2, C(O)NHOH, C(O)NHOR.sup.13,
C(O)NHSO.sub.2R.sup.13, C(O)NR.sup.13SO.sub.2R.sup.13,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.13, SO.sub.2N(R.sup.13).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0341] R.sup.13 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected R.sup.14, OR.sup.14, SR.sup.14, S(O)R.sup.14,
SO.sub.2R.sup.14, C(O)R.sup.14, CO(O)R.sup.14, OC(O)R.sup.14,
OC(O)OR.sup.14, NH.sub.2, NHR.sup.14, N(R.sup.14).sub.2,
NHC(O)R.sup.14, NR.sup.14C(O)R.sup.14, NHS(O).sub.2R.sup.14,
NR.sup.14S(O).sub.2R.sup.14, NHC(O)OR.sup.14,
NR.sup.14C(O)OR.sup.14, NHC(O)NH.sub.2, NHC(O)NHR.sup.14,
NHC(O)N(R.sup.14).sub.2, NR.sup.14C(O)NHR.sup.14,
NR.sup.14C(O)N(R.sup.14).sub.2, C(O)NH.sub.2, C(O)NHR.sup.14,
C(O)N(R.sup.14).sub.2, C(O)NHOH, C(O)NHOR.sup.14,
C(O)NHSO.sub.2R.sup.14, C(O)NR.sup.14SO.sub.2R.sup.14,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.14, SO.sub.2N(R.sup.14).sub.2,
C(O)H, C(O)OH, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
wherein each aryl, heterocyclyl, cycloalkyl, and cycloalkenyl is
optionally substituted with one or more independently selected
R.sup.15, OR.sup.15, SR.sup.15, S(O)R.sup.15, SO.sub.2R.sup.15,
C(O)R.sup.15, CO(O)R.sup.15, OC(O)R.sup.15, OC(O)OR.sup.15,
NH.sub.2, NHR.sup.15, N(R.sup.15).sub.2, NHC(O)R.sup.15,
NR.sup.15C(O)R.sup.15, NHS(O).sub.2R.sup.15,
NR.sup.15S(O).sub.2R.sup.15, NHC(O)OR.sup.15,
NR.sup.15C(O)OR.sup.15, NHC(O)NH.sub.2, NHC(O)NHR.sup.15,
NHC(O)N(R.sup.15).sub.2, NR.sup.15C(O)NHR.sup.15,
NR.sup.15C(O)N(R.sup.15).sub.2, C(O)NH.sub.2, C(O)NHR.sup.15,
C(O)N(R.sup.15).sub.2, C(O)NHOH, C(O)NHOR.sup.15,
C(O)NHSO.sub.2R.sup.15, C(O)NR.sup.15SO.sub.2R.sup.15,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.15, SO.sub.2N(R.sup.15).sub.2,
C(O)H, C(O)OH, OH, CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0342] R.sup.14 is alkyl, alkenyl, alkynyl, aryl, heterocyclyl,
cycloalkyl, or cycloalkenyl; wherein each alkyl, alkenyl, and
alkynyl is optionally substituted with one or more independently
selected NH.sub.2, SO.sub.2NH.sub.2, C(O)H, C(O)OH, OH, (O), CN,
N.sub.3, NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3,
OCF.sub.2CF.sub.3, F, Cl, Br or I; and
[0343] R.sup.15 is alkyl.
[0344] In one embodiment of Formula (I), X.sup.1, X.sup.2 and
X.sup.3 are CH; or X.sup.1 and X.sup.3 are CH and X.sup.2 is N; or
X.sup.2 and X.sup.3 are CH and X.sup.1 is N; or X.sup.1 is CR.sup.1
and X.sup.2 and X.sup.3 are CH; or X.sup.2 is CR.sup.1 and X.sup.1
and X.sup.3 are CH; or X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2
are CH.
[0345] In another embodiment of Formula (I), X.sup.1, X.sup.2 and
X.sup.3 are CH. In another embodiment of Formula (I), X.sup.1 and
X.sup.3 are CH and X.sup.2 is N. In another embodiment of Formula
(I), X.sup.2 and X.sup.3 are CH and X.sup.1 is N. In another
embodiment of Formula (I), X.sup.1 is CR.sup.1 and X.sup.2 and
X.sup.3 are CH. In another embodiment of Formula (I), X.sup.2 is
CR.sup.1 and X.sup.1 and X.sup.3 are CH. In another embodiment of
Formula (I), X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are
CH.
[0346] In one embodiment of Formula (I), R.sup.1 is
NHSO.sub.2R.sup.3, F, Cl, Br, or I. In another embodiment of
Formula (I), R.sup.1 is F. In another embodiment of Formula (I),
R.sup.1 is NHSO.sub.2R.sup.3; and R.sup.3 is alkyl.
[0347] In one embodiment of Formula (I), X.sup.1 is CR.sup.1;
X.sup.2 and X.sup.3 are CH; and R.sup.1 is F. In one embodiment of
Formula (I), X.sup.2 is CR.sup.1; X.sup.1 and X.sup.3 are CH; and
R.sup.1 is F. In another embodiment of Formula (I), X.sup.3 is
CR.sup.1; and X.sup.1 and X.sup.2 are CH; and R.sup.1 is
NHSO.sub.2R.sup.3; and R.sup.3 is alkyl.
[0348] In one embodiment of Formula (I),
[0349] X.sup.1 and X.sup.2 and X.sup.3 are CH; or
[0350] X.sup.1 and X.sup.3 are CH; and X.sup.2 is N; or
[0351] X.sup.2 and X.sup.3 are H; and X.sup.1 is N; or
[0352] X.sup.1 is CR.sup.1; and X.sup.2 and X.sup.3 are CH; or
[0353] X.sup.2 is CR.sup.1; and X.sup.1 and X.sup.3 are CH; or
[0354] X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are CH;
[0355] R.sup.1 is NHSO.sub.2R.sup.3, F, Cl, Br, or I;
[0356] R.sup.2 is alkyl, phenyl, or heterocyclyl; wherein each
alkyl is optionally substituted with CO(O)R.sup.4; wherein each
phenyl is optionally additionally substituted at the para position
with one independently selected R.sup.5, C(O)R.sup.5,
NHC(O)R.sup.5, or C(O)NHR.sup.5; wherein each heterocyclyl is
optionally substituted with C(O)NHR.sup.5; wherein R.sup.2 is not
4-methylphenyl;
[0357] R.sup.3 is alkyl;
[0358] R.sup.4 is alkyl;
[0359] R.sup.5 is alkyl, alkenyl, aryl, heterocyclyl, or
cycloalkyl; wherein each alkyl and alkenyl, is optionally
substituted with one or more independently selected R.sup.9,
OR.sup.9, SR.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9, N(R.sup.9).sub.2,
NHC(O)R.sup.9, C(O)NHR.sup.9, OH, or CF.sub.3, F, Cl, Br or I;
[0360] R.sup.9 is alkyl, aryl, heterocyclyl, or cycloalkyl; wherein
each alkyl is optionally substituted with one or more independently
selected OCH.sub.3, aryl, or heterocyclyl;
[0361] wherein the cyclic moieties represented by R.sup.5 and
R.sup.9 are optionally substituted with one or more independently
selected R.sup.13, OR.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, NH.sub.2, C(O)NHR.sup.13, F, Cl, Br or I;
[0362] R.sup.13 is alkyl, aryl, or heterocyclyl; wherein each alkyl
is optionally substituted with one or more independently selected
R.sup.14, OH, F, Cl, Br or I; and
[0363] R.sup.14 is aryl F, Cl, Br or I.
[0364] Still another embodiment pertains to compounds having
Formula (I), which include [0365]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0366]
N-(4-{[4-(pyridin-2-yl)piperazin-1-yl]carbonyl}phenyl)-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0367]
6-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0368]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1-
H)-carboxamide; [0369]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1H-
)-carboxamide; [0370]
6-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0371]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0372]
N-[4-(benzylcarbamoyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0373]
N-{5-[(3-phenylpropyl)carbamoyl]pyridin-2-yl}-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0374]
N-{5-[(3-methylbutyl)carbamoyl]pyridin-2-yl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0375]
N-(4-{[1-(3-methylbutyl)-1H-pyrazol-4-yl]carbamoyl}phenyl)-3,4-dihydroiso-
quinoline-2(1H)-carboxamide; [0376]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,6-naphthyridine-
-2(1H)-carboxamide; [0377]
6-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0378]
N-{4-[(1-benzyl-1H-pyrazol-4-yl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0379]
N-{4-[(2-phenylethyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0380]
7-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0381]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0382]
N-{6-[(3-methylbutyl)carbamoyl]pyridin-3-yl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0383]
N-(5-{[2-(2-thienyl)ethyl]carbamoyl}pyridin-2-yl)-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0384]
7-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0385]
N-{6-[(3-phenylpropyl)carbamoyl]pyridin-3-yl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide; [0386]
N-(6-{[2-(2-thienyl)ethyl]carbamoyl}pyridin-3-yl)-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0387]
7-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0388]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1-
H)-carboxamide; [0389]
N-[4-(2-oxo-2-{[2-(2-thienyl)ethyl]amino}ethyl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0390]
N-(4-{2-oxo-2-[(3-phenylpropyl)amino]ethyl}phenyl)-3,4-dihydroisoquinolin-
e-2(1H)-carboxamide; [0391]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1H-
)-carboxamide; [0392]
N-(4-{2-[(3-methylbutyl)amino]-2-oxoethyl}phenyl)-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0393]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,7-naphthyridine-
-2(1H)-carboxamide; [0394]
N-{4-[(4-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0395]
N-{4-[(4-phenylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0396]
N-(4-{[3-(2-thienyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0397]
N-[4-(1-isobutyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-ca-
rboxamide; [0398]
N-[4-(1-propyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0399]
N-{4-[1-((2R)-2-hydroxypropyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0400]
N-{4-[1-(3-methylbutyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0401]
N-[4-(1-benzyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0402]
N-{4-[(1E)-5-phenylpent-1-en-1-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0403]
N-[4-(1-ethyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0404]
N-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0405]
N-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0406]
N-[4-(1-benzoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0407]
N-[4-(1-butyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0408]
N-{4-[1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-di-
hydroisoquinoline-2(1H)-carboxamide; [0409]
N-[4-(1-isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoq-
uinoline-2(1H)-carboxamide; [0410]
N-{4-[1-(3-methylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide; [0411]
N-{4-[1-(methylcarbamoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihy-
droisoquinoline-2(1H)-carboxamide; [0412] tert-butyl
4-{4-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]phenyl}-3,6-dihydrop-
yridine-1(2H)-carboxylate; [0413]
N-[4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0414]
N-{4-[1-(isobutylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide; [0415]
N-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0416]
N-{4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide; [0417]
N-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0418]
N-{4-[1-(3-methylbutyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydr-
oisoquinoline-2(1H)-carboxamide; [0419]
N-[4-(5-propyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0420]
N-[4-(5-benzyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0421]
N-{4-[5-(3-methylbutyl)-1,2,4-oxadiazol-3-yl]phenyl}-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0422]
N-hexyl-3,4-dihydroisoquinoline-2(1H)-carboxamide; [0423] ethyl
6-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]hexanoate; [0424]
N-(4-{2-[(phenylacetyl)amino]ethyl}phenyl)-3,4-dihydroisoquinoline-2(1H)--
carboxamide; [0425]
N-{4-[2-(isobutyrylamino)ethyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0426]
N-(4-{[(benzyloxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0427]
N-(4-{[(4-methoxycyclohexyl)carbonyl]amino}phenyl)-3,4-dihydroisoquinolin-
e-2(1H)-carboxamide; [0428]
N-(4-{[(1-acetylpiperidin-4-yl)carbonyl]amino}phenyl)-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0429]
N-(4-{[4-oxo-4-(2-thienyl)butanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0430]
N-(4-{[3-(phenylsulfonyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0431]
N-{4-[((2R)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide and
N-{4-[((2S)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide; [0432] N
N-{4-[((3R)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide and
N-{4-[((3S)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0433]
N-{4-[(2,2-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0434]
N-{4-[(3,3-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0435]
N-[4-(heptanoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0436]
N-{4-[(4,4,4-trifluorobutanoyl)amino]phenyl}-3,4-dihydroisoquinoli-
ne-2(1H)-carboxamide; [0437]
N-(4-{[(2-methoxyethoxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0438]
N-{4-[((3R)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide and
N-{4-[((3S)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0439]
N-(4-{[3-(methylthio)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0440]
N-{4-[(cyclopentylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0441]
N-{4-[(cyclohexylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0442]
N-{4-[(cyclohexylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0443]
N-[4-(benzoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0444]
N-{4-[(phenylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-ca-
rboxamide; [0445]
N-(4-{[3-(4-aminophenyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0446]
N-[4-(3-furoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0447]
N-{4-[(2,5-dimethyl-3-furoyl)amino]phenyl}-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0448]
N-{4-[(3-thienylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0449]
N-{4-[(1H-pyrrol-2-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0450]
N-{4-[(1,3-thiazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide; [0451]
N-{4-[(1H-pyrazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0452]
N-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0453]
N-{4-[(1,2-oxazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0454]
N-{4-[(pyridin-2-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0455]
N-{4-[(N,N-dimethyl-beta-alanyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide; [0456]
N-(4-{[3-(piperidin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0457]
N-{4-[(morpholin-4-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0458]
N-(4-{[3-(morpholin-4-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0459]
N-(4-{[3-(4-methylpiperazin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoqu-
inoline-2(1H)-carboxamide; [0460]
N-[4-(trifluoromethyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0461]
N-{4-[(cyclopentylacetyl)amino]phenyl}-5-[(methylsulfonyl)amino]-3-
,4-dihydroisoquinoline-2(1H)-carboxamide; and pharmaceutically
acceptable salts thereof.
Embodiments of Formula (II)
[0462] In another aspect, the present invention provides compounds
of Formula (II)
##STR00007##
and pharmaceutically acceptable salts thereof; wherein X.sup.1,
X.sup.2, and X.sup.3 are as described herein for Formula (I); and
R.sup.2 is phenyl, heterocyclyl, cycloalkyl, or cycloalkenyl;
wherein the phenyl, heterocyclyl, cycloalkyl, and cycloalkenyl are
optionally substituted as described herein for Formula (I).
[0463] In one embodiment of Formula (II), X.sup.1, X.sup.2 and
X.sup.3 are CH; or X.sup.1 and X.sup.3 are CH and X.sup.2 is N; or
X.sup.2 and X.sup.3 are CH and X.sup.1 is N; or X.sup.1 is CR.sup.1
and X.sup.2 and X.sup.3 are CH; or X.sup.2 is CR.sup.1 and X.sup.1
and X.sup.3 are CH; or X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2
are CH.
[0464] In another embodiment of Formula (II), X.sup.1, X.sup.2 and
X.sup.3 are CH. In another embodiment of Formula (II), X.sup.1 and
X.sup.3 are CH and X.sup.2 is N. In another embodiment of Formula
(II), X.sup.2 and X.sup.3 are CH and X.sup.1 is N. In another
embodiment of Formula (II), X.sup.1 is CR.sup.1 and X.sup.2 and
X.sup.3 are CH. In another embodiment of Formula (II), X.sup.2 is
CR.sup.1 and X.sup.1 and X.sup.3 are CH. In another embodiment of
Formula (II), X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are
CH.
[0465] In one embodiment of Formula (II), R.sup.1 is
NHSO.sub.2R.sup.3, F, Cl, Br, or I. In another embodiment of
Formula (II), R.sup.1 is F. In another embodiment of Formula (II),
R.sup.1 is NHSO.sub.2R.sup.3; and R.sup.3 is alkyl.
[0466] In one embodiment of Formula (II), X.sup.1 is CR.sup.1;
X.sup.2 and X.sup.3 are CH; and R.sup.1 is F. In one embodiment of
Formula (II), X.sup.2 is CR.sup.1; X.sup.1 and X.sup.3 are CH; and
R.sup.1 is F. In another embodiment of Formula (II), X.sup.3 is
CR.sup.1; and X.sup.1 and X.sup.2 are CH; and R.sup.1 is
NHSO.sub.2R.sup.3; and R.sup.3 is alkyl.
[0467] In one embodiment of Formula (II),
[0468] X.sup.1 and X.sup.2 and X.sup.3 are CH; or
[0469] X.sup.1 and X.sup.3 are CH; and X.sup.2 is N; or
[0470] X.sup.2 and X.sup.3 are H; and X.sup.1 is N; or
[0471] X.sup.1 is CR.sup.1; and X.sup.2 and X.sup.3 are CH; or
[0472] X.sup.2 is CR.sup.1; and X.sup.1 and X.sup.3 are CH; or
[0473] X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are CH;
[0474] R.sup.1 is NHSO.sub.2R.sup.3, F, Cl, Br, or I;
[0475] R.sup.2 is phenyl, or heterocyclyl; wherein each phenyl is
optionally additionally substituted at the para position with one
independently selected R.sup.5, C(O)R.sup.5, NHC(O)R.sup.5, or
C(O)NHR.sup.5; wherein each heterocyclyl is optionally substituted
with C(O)NHR.sup.5; wherein R.sup.2 is not 4-methylphenyl;
[0476] R.sup.3 is alkyl;
[0477] R.sup.5 is alkyl, alkenyl, aryl, heterocyclyl, or
cycloalkyl; wherein each alkyl and alkenyl, is optionally
substituted with one or more independently selected R.sup.9,
OR.sup.9, SR.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9, N(R.sup.9).sub.2,
NHC(O)R.sup.9, C(O)NHR.sup.9, OH, or CF.sub.3, F, Cl, Br or I;
[0478] R.sup.9 is alkyl, aryl, heterocyclyl, or cycloalkyl; wherein
each alkyl is optionally substituted with one or more independently
selected OCH.sub.3, aryl, or heterocyclyl;
[0479] wherein the cyclic moieties represented by R.sup.5 and
R.sup.9 are optionally substituted with one or more independently
selected R.sup.13, OR.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, NH.sub.2, C(O)NHR.sup.13, F, Cl, Br or I;
[0480] R.sup.13 is alkyl, aryl, or heterocyclyl; wherein each alkyl
is optionally substituted with one or more independently selected
R.sup.14, OH, F, Cl, Br or I; and
[0481] R.sup.14 is aryl F, Cl, Br or I.
[0482] Still another embodiment pertains to compounds having
Formula (II), which include [0483]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0484]
N-(4-{[4-(pyridin-2-yl)piperazin-1-yl]carbonyl}phenyl)-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0485]
6-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0486]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1-
H)-carboxamide; [0487]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1H-
)-carboxamide; [0488]
6-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0489]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0490]
N-[4-(benzylcarbamoyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0491]
N-{5-[(3-phenylpropyl)carbamoyl]pyridin-2-yl}-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0492]
N-{5-[(3-methylbutyl)carbamoyl]pyridin-2-yl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0493]
N-(4-{[1-(3-methylbutyl)-1H-pyrazol-4-yl]carbamoyl}phenyl)-3,4-dihydroiso-
quinoline-2(1H)-carboxamide; [0494]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,6-naphthyridine-
-2(1H)-carboxamide; [0495]
6-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0496]
N-{4-[(1-benzyl-1H-pyrazol-4-yl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0497]
N-{4-[(2-phenylethyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0498]
7-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0499]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0500]
N-{6-[(3-methylbutyl)carbamoyl]pyridin-3-yl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0501]
N-(5-{[2-(2-thienyl)ethyl]carbamoyl}pyridin-2-yl)-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0502]
7-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0503]
N-{6-[(3-phenylpropyl)carbamoyl]pyridin-3-yl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide; [0504]
N-(6-{[2-(2-thienyl)ethyl]carbamoyl}pyridin-3-yl)-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0505]
7-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0506]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1-
H)-carboxamide; [0507]
N-[4-(2-oxo-2-{[2-(2-thienyl)ethyl]amino}ethyl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0508]
N-(4-{2-oxo-2-[(3-phenylpropyl)amino]ethyl}phenyl)-3,4-dihydroisoquinolin-
e-2(1H)-carboxamide; [0509]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1H-
)-carboxamide; [0510]
N-(4-{2-[(3-methylbutyl)amino]-2-oxoethyl}phenyl)-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0511]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,7-naphthyridine-
-2(1H)-carboxamide; [0512]
N-{4-[(4-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0513]
N-{4-[(4-phenylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0514]
N-(4-{[3-(2-thienyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0515]
N-[4-(1-isobutyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-ca-
rboxamide; [0516]
N-[4-(1-propyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0517]
N-{4-[1-((2R)-2-hydroxypropyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0518]
N-{4-[1-(3-methylbutyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0519]
N-[4-(1-benzyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0520]
N-{4-[(1E)-5-phenylpent-1-en-1-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0521]
N-[4-(1-ethyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0522]
N-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0523]
N-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0524]
N-[4-(1-benzoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0525]
N-[4-(1-butyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0526]
N-{4-[1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-di-
hydroisoquinoline-2(1H)-carboxamide; [0527]
N-[4-(1-isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoq-
uinoline-2(1H)-carboxamide; [0528]
N-{4-[1-(3-methylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide; [0529]
N-{4-[1-(methylcarbamoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihy-
droisoquinoline-2(1H)-carboxamide; [0530] tert-butyl
4-{4-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]phenyl}-3,6-dihydrop-
yridine-1(2H)-carboxylate; [0531]
N-[4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0532]
N-{4-[1-(isobutylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide; [0533]
N-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0534]
N-{4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide; [0535]
N-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0536]
N-{4-[1-(3-methylbutyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydr-
oisoquinoline-2(1H)-carboxamide; [0537]
N-[4-(5-propyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0538]
N-[4-(5-benzyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0539] ethyl
6-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]hexanoate; [0540]
N-(4-{2-[(phenylacetyl)amino]ethyl}phenyl)-3,4-dihydroisoquinoline-2(1H)--
carboxamide; [0541]
N-{4-[2-(isobutyrylamino)ethyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0542]
N-(4-{[(benzyloxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0543]
N-(4-{[(4-methoxycyclohexyl)carbonyl]amino}phenyl)-3,4-dihydroisoquinolin-
e-2(1H)-carboxamide; [0544]
N-(4-{[(1-acetylpiperidin-4-yl)carbonyl]amino}phenyl)-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0545]
N-(4-{[4-oxo-4-(2-thienyl)butanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0546]
N-(4-{[3-(phenylsulfonyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0547]
N-{4-[((2R)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide and
N-{4-[((2S)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide; [0548] N
N-{4-[((3R)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide and
N-{4-[((3S)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0549]
N-{4-[(2,2-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0550]
N-{4-[(3,3-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0551]
N-[4-(heptanoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0552]
N-{4-[(4,4,4-trifluorobutanoyl)amino]phenyl}-3,4-dihydroisoquinoli-
ne-2(1H)-carboxamide; [0553]
N-(4-{[(2-methoxyethoxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0554]
N-{4-[((3R)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide and
N-{4-[((3S)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0555]
N-(4-{[3-(methylthio)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0556]
N-{4-[(cyclopentylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0557]
N-{4-[(cyclohexylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0558]
N-{4-[(cyclohexylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0559]
N-[4-(benzoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0560]
N-{4-[(phenylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-ca-
rboxamide; [0561]
N-(4-{[3-(4-aminophenyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0562]
N-[4-(3-furoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0563]
N-{4-[(2,5-dimethyl-3-furoyl)amino]phenyl}-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0564]
N-{4-[(3-thienylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0565]
N-{4-[(1H-pyrrol-2-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0566]
N-{4-[(1,3-thiazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide; [0567]
N-{4-[(1H-pyrazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0568]
N-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0569]
N-{4-[(1,2-oxazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0570]
N-{4-[(pyridin-2-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0571]
N-{4-[(N,N-dimethyl-beta-alanyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide; [0572]
N-(4-{[3-(piperidin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0573]
N-{4-[(morpholin-4-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0574]
N-(4-{[3-(morpholin-4-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0575]
N-(4-{[3-(4-methylpiperazin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoqu-
inoline-2(1H)-carboxamide; [0576]
N-[4-(trifluoromethyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0577]
N-{4-[(cyclopentylacetyl)amino]phenyl}-5-[(methylsulfonyl)amino]-3-
,4-dihydroisoquinoline-2(1H)-carboxamide; and pharmaceutically
acceptable salts thereof.
Embodiments of Formula (III)
[0578] In another aspect, the present invention provides compounds
of Formula (III)
##STR00008##
and pharmaceutically acceptable salts thereof; wherein X.sup.1,
X.sup.2, and X.sup.3 are as described herein for Formula (I); and
R.sup.X is as described herein for substituents in Formula (I) when
R.sup.2 is phenyl.
[0579] In one embodiment of Formula (III), X.sup.1, X.sup.2 and
X.sup.3 are CH; or X.sup.1 and X.sup.3 are CH and X.sup.2 is N; or
X.sup.2 and X.sup.3 are CH and X.sup.1 is N; or X.sup.1 is CR.sup.1
and X.sup.2 and X.sup.3 are CH; or X.sup.2 is CR.sup.1 and X.sup.1
and X.sup.3 are CH; or X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2
are CH.
[0580] In another embodiment of Formula (III), X.sup.1, X.sup.2 and
X.sup.3 are CH. In another embodiment of Formula (III), X.sup.1 and
X.sup.3 are CH and X.sup.2 is N. In another embodiment of Formula
(III), X.sup.2 and X.sup.3 are CH and X.sup.1 is N. In another
embodiment of Formula (III), X.sup.1 is CR.sup.1 and X.sup.2 and
X.sup.3 are CH. In another embodiment of Formula (III), X.sup.2 is
CR.sup.1 and X.sup.1 and X.sup.3 are CH. In another embodiment of
Formula (III), X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are
CH.
[0581] In one embodiment of Formula (III), R.sup.1 is
NHSO.sub.2R.sup.3, F, Cl, Br, or I. In another embodiment of
Formula (III), R.sup.1 is F. In another embodiment of Formula
(III), R.sup.1 is NHSO.sub.2R.sup.3; and R.sup.3 is alkyl.
[0582] In one embodiment of Formula (III), X.sup.1 is CR.sup.1;
X.sup.2 and X.sup.3 are CH; and R.sup.1 is F. In one embodiment of
Formula (III), X.sup.2 is CR.sup.1; X.sup.1 and X.sup.3 are CH; and
R.sup.1 is F. In another embodiment of Formula (III), X.sup.3 is
CR.sup.1; and X.sup.1 and X.sup.2 are CH; and R.sup.1 is
NHSO.sub.2R.sup.3; and R.sup.3 is alkyl.
[0583] In one embodiment of Formula (III),
[0584] X.sup.1 and X.sup.2 and X.sup.3 are CH; or
[0585] X.sup.1 and X.sup.3 are CH; and X.sup.2 is N; or
[0586] X.sup.2 and X.sup.3 are H; and X.sup.1 is N; or
[0587] X.sup.1 is CR.sup.1; and X.sup.2 and X.sup.3 are CH; or
[0588] X.sup.2 is CR.sup.1; and X.sup.1 and X.sup.3 are CH; or
[0589] X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are CH;
[0590] R.sup.1 is NHSO.sub.2R.sup.3, F, Cl, Br, or I;
[0591] R.sup.3 is alkyl;
[0592] R.sup.x is R.sup.5, C(O)R.sup.5, NHC(O)R.sup.5, or
C(O)NHR.sup.5; wherein R.sup.x is not methyl;
[0593] R.sup.5 is alkyl, alkenyl, aryl, heterocyclyl, or
cycloalkyl; wherein each alkyl and alkenyl, is optionally
substituted with one or more independently selected R.sup.9,
OR.sup.9, SR.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9, N(R.sup.9).sub.2,
NHC(O)R.sup.9, C(O)NHR.sup.9, OH, or CF.sub.3, F, Cl, Br or I;
[0594] R.sup.9 is alkyl, aryl, heterocyclyl, or cycloalkyl; wherein
each alkyl is optionally substituted with one or more independently
selected OCH.sub.3, aryl, or heterocyclyl;
[0595] wherein the cyclic moieties represented by R.sup.5 and
R.sup.9 are optionally substituted with one or more independently
selected R.sup.13, OR.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, NH.sub.2, C(O)NHR.sup.13, F, Cl, Br or I;
[0596] R.sup.13 is alkyl, aryl, or heterocyclyl; wherein each alkyl
is optionally substituted with one or more independently selected
R.sup.14, OH, F, Cl, Br or I; and
[0597] R.sup.14 is aryl F, Cl, Br or I.
[0598] Still another embodiment pertains to compounds having
Formula (III), which include [0599]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0600]
N-(4-{[4-(pyridin-2-yl)piperazin-1-yl]carbonyl}phenyl)-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0601]
6-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0602]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1-
H)-carboxamide; [0603]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1H-
)-carboxamide; [0604]
6-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0605]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0606]
N-[4-(benzylcarbamoyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0607]
N-(4-{[1-(3-methylbutyl)-1H-pyrazol-4-yl]carbamoyl}phenyl)-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide; [0608]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,6-naphthyridine-
-2(1H)-carboxamide; [0609]
6-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0610]
N-{4-[(1-benzyl-1H-pyrazol-4-yl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0611]
N-{4-[(2-phenylethyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0612]
7-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0613]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0614]
7-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0615]
7-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0616]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1-
H)-carboxamide; [0617]
N-[4-(2-oxo-2-{[2-(2-thienyl)ethyl]amino}ethyl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0618]
N-(4-{2-oxo-2-[(3-phenylpropyl)amino]ethyl}phenyl)-3,4-dihydroisoquinolin-
e-2(1H)-carboxamide; [0619]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1H-
)-carboxamide; [0620]
N-(4-{2-[(3-methylbutyl)amino]-2-oxoethyl}phenyl)-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0621]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,7-naphthyridine-
-2(1H)-carboxamide; [0622]
N-{4-[(4-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0623]
N-{4-[(4-phenylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0624]
N-(4-{[3-(2-thienyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0625]
N-[4-(1-isobutyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-ca-
rboxamide; [0626]
N-[4-(1-propyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0627]
N-{4-[1-((2R)-2-hydroxypropyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0628]
N-{4-[1-(3-methylbutyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0629]
N-[4-(1-benzyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0630]
N-{4-[(1E)-5-phenylpent-1-en-1-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0631]
N-[4-(1-ethyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0632]
N-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0633]
N-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0634]
N-[4-(1-benzoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0635]
N-[4-(1-butyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0636]
N-{4-[1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-di-
hydroisoquinoline-2(1H)-carboxamide; [0637]
N-[4-(1-isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoq-
uinoline-2(1H)-carboxamide; [0638]
N-{4-[1-(3-methylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide; [0639]
N-{4-[1-(methylcarbamoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihy-
droisoquinoline-2(1H)-carboxamide; [0640] tert-butyl
4-{4-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]phenyl}-3,6-dihydrop-
yridine-1(2H)-carboxylate; [0641]
N-[4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0642]
N-{4-[1-(isobutylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide; [0643]
N-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0644]
N-{4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide; [0645]
N-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0646]
N-{4-[1-(3-methylbutyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydr-
oisoquinoline-2(1H)-carboxamide; [0647]
N-[4-(5-propyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0648]
N-[4-(5-benzyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0649] ethyl
6-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]hexanoate; [0650]
N-(4-{2-[(phenylacetyl)amino]ethyl}phenyl)-3,4-dihydroisoquinoline-2(1H)--
carboxamide; [0651]
N-{4-[2-(isobutyrylamino)ethyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0652]
N-(4-{[(benzyloxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0653]
N-(4-{[(4-methoxycyclohexyl)carbonyl]amino}phenyl)-3,4-dihydroisoquinolin-
e-2(1H)-carboxamide; [0654]
N-(4-{[(1-acetylpiperidin-4-yl)carbonyl]amino}phenyl)-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0655]
N-(4-{[4-oxo-4-(2-thienyl)butanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0656]
N-(4-{[3-(phenylsulfonyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0657]
N-{4-[((2R)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide and
N-{4-[((2S)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide; [0658] N
N-{4-[((3R)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide and
N-{4-[((3S)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0659]
N-{4-[(2,2-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0660]
N-{4-[(3,3-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0661]
N-[4-(heptanoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0662]
N-{4-[(4,4,4-trifluorobutanoyl)amino]phenyl}-3,4-dihydroisoquinoli-
ne-2(1H)-carboxamide; [0663]
N-(4-{[(2-methoxyethoxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0664]
N-{4-[((3R)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide and
N-{4-[((3S)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0665]
N-(4-{[3-(methylthio)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0666]
N-{4-[(cyclopentylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0667]
N-{4-[(cyclohexylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0668]
N-{4-[(cyclohexylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0669]
N-[4-(benzoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0670]
N-{4-[(phenylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-ca-
rboxamide; [0671]
N-(4-{[3-(4-aminophenyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0672]
N-[4-(3-furoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0673]
N-{4-[(2,5-dimethyl-3-furoyl)amino]phenyl}-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0674]
N-{4-[(3-thienylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0675]
N-{4-[(1H-pyrrol-2-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0676]
N-{4-[(1,3-thiazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide; [0677]
N-{4-[(1H-pyrazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0678]
N-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0679]
N-{4-[(1,2-oxazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0680]
N-{4-[(pyridin-2-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0681]
N-{4-[(N,N-dimethyl-beta-alanyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide; [0682]
N-(4-{[3-(piperidin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0683]
N-{4-[(morpholin-4-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0684]
N-(4-{[3-(morpholin-4-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0685]
N-(4-{[3-(4-methylpiperazin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoqu-
inoline-2(1H)-carboxamide; [0686]
N-[4-(trifluoromethyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0687]
N-{4-[(cyclopentylacetyl)amino]phenyl}-5-[(methylsulfonyl)amino]-3-
,4-dihydroisoquinoline-2(1H)-carboxamide; and pharmaceutically
acceptable salts thereof.
Embodiments of Formula (IV)
[0688] In another aspect, the present invention provides compounds
of Formula (IV)
##STR00009##
and pharmaceutically acceptable salts thereof; wherein X.sup.1,
X.sup.2, X.sup.3 and R.sup.5 are as described herein for Formula
(I).
[0689] In one embodiment of Formula (IV), X.sup.1, X.sup.2 and
X.sup.3 are CH; or X.sup.1 and X.sup.3 are CH and X.sup.2 is N; or
X.sup.2 and X.sup.3 are CH and X.sup.1 is N; or X.sup.1 is CR.sup.1
and X.sup.2 and X.sup.3 are CH; or X.sup.2 is CR.sup.1 and X.sup.1
and X.sup.3 are CH; or X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2
are CH.
[0690] In another embodiment of Formula (IV), X.sup.1, X.sup.2 and
X.sup.3 are CH. In another embodiment of Formula (IV), X.sup.1 and
X.sup.3 are CH and X.sup.2 is N. In another embodiment of Formula
(IV), X.sup.2 and X.sup.3 are CH and X.sup.1 is N. In another
embodiment of Formula (IV), X.sup.1 is CR.sup.1 and X.sup.2 and
X.sup.3 are CH. In another embodiment of Formula (IV), X.sup.2 is
CR.sup.1 and X.sup.1 and X.sup.3 are CH. In another embodiment of
Formula (IV), X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are
CH.
[0691] In one embodiment of Formula (IV), R.sup.1 is
NHSO.sub.2R.sup.3, F, Cl, Br, or I. In another embodiment of
Formula (IV), R.sup.1 is F. In another embodiment of Formula (IV),
R.sup.1 is NHSO.sub.2R.sup.3; and R.sup.3 is alkyl.
[0692] In one embodiment of Formula (IV), X.sup.1 is CR.sup.1;
X.sup.2 and X.sup.3 are CH; and R.sup.1 is F. In one embodiment of
Formula (IV), X.sup.2 is CR.sup.1; X.sup.1 and X.sup.3 are CH; and
R.sup.1 is F. In another embodiment of Formula (IV), X.sup.3 is
CR.sup.1; and X.sup.1 and X.sup.2 are CH; and R.sup.1 is
NHSO.sub.2R.sup.3; and R.sup.3 is alkyl.
[0693] In one embodiment of Formula (IV),
[0694] X.sup.1 and X.sup.2 and X.sup.3 are CH; or
[0695] X.sup.1 and X.sup.3 are CH; and X.sup.2 is N; or
[0696] X.sup.2 and X.sup.3 are H; and X.sup.1 is N; or
[0697] X.sup.1 is CR.sup.1; and X.sup.2 and X.sup.3 are CH; or
[0698] X.sup.2 is CR.sup.1; and X.sup.1 and X.sup.3 are CH; or
[0699] X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are CH;
[0700] R.sup.1 is NHSO.sub.2R.sup.3, F, Cl, Br, or I;
[0701] R.sup.3 is alkyl;
[0702] R.sup.5 is alkyl, alkenyl, aryl, heterocyclyl, or
cycloalkyl; wherein each alkyl and alkenyl, is optionally
substituted with one or more independently selected R.sup.9,
OR.sup.9, SR.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9, N(R.sup.9).sub.2,
NHC(O)R.sup.9, C(O)NHR.sup.9, OH, or CF.sub.3, F, Cl, Br or I;
[0703] R.sup.9 is alkyl, aryl, heterocyclyl, or cycloalkyl; wherein
each alkyl is optionally substituted with one or more independently
selected OCH.sub.3, aryl, or heterocyclyl;
[0704] wherein the cyclic moieties represented by R.sup.5 and
R.sup.9 are optionally substituted with one or more independently
selected R.sup.13, OR.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, NH.sub.2, (O)NHR.sup.13, F, Cl, Br or I;
[0705] R.sup.13 is alkyl, aryl, or heterocyclyl; wherein each alkyl
is optionally substituted with one or more independently selected
R.sup.14, OH, F, Cl, Br or I; and
[0706] R.sup.14 is aryl F, Cl, Br or I.
[0707] Still another embodiment pertains to compounds having
Formula (IV), which include [0708]
N-{4-[(4-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0709]
N-{4-[(4-phenylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0710]
N-(4-{[3-(2-thienyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0711]
N-(4-{[(benzyloxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0712]
N-(4-{[(4-methoxycyclohexyl)carbonyl]amino}phenyl)-3,4-dihydroisoquinolin-
e-2(1H)-carboxamide; [0713]
N-(4-{[(1-acetylpiperidin-4-yl)carbonyl]amino}phenyl)-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0714]
N-(4-{[4-oxo-4-(2-thienyl)butanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0715]
N-(4-{[3-(phenylsulfonyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0716]
N-{4-[((2R)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide and
N-{4-[((2S)-2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide; [0717] N
N-{4-[((3R)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide and
N-{4-[((3S)-3-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0718]
N-{4-[(2,2-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0719]
N-{4-[(3,3-dimethylbutanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0720]
N-[4-(heptanoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0721]
N-{4-[(4,4,4-trifluorobutanoyl)amino]phenyl}-3,4-dihydroisoquinoli-
ne-2(1H)-carboxamide; [0722]
N-(4-{[(2-methoxyethoxy)acetyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0723]
N-{4-[((3R)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide and
N-{4-[((3S)-tetrahydrofuran-3-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0724]
N-(4-{[3-(methylthio)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0725]
N-{4-[(cyclopentylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0726]
N-{4-[(cyclohexylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0727]
N-{4-[(cyclohexylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide; [0728]
N-[4-(benzoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0729]
N-{4-[(phenylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-ca-
rboxamide; [0730]
N-(4-{[3-(4-aminophenyl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0731]
N-[4-(3-furoylamino)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0732]
N-{4-[(2,5-dimethyl-3-furoyl)amino]phenyl}-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0733]
N-{4-[(3-thienylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0734]
N-{4-[(1H-pyrrol-2-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0735]
N-{4-[(1,3-thiazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide; [0736]
N-{4-[(1H-pyrazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0737]
N-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0738]
N-{4-[(1,2-oxazol-5-ylcarbonyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide; [0739]
N-{4-[(pyridin-2-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0740]
N-{4-[(N,N-dimethyl-beta-alanyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1-
H)-carboxamide; [0741]
N-(4-{[3-(piperidin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0742]
N-{4-[(morpholin-4-ylacetyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide; [0743]
N-(4-{[3-(morpholin-4-yl)propanoyl]amino}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0744]
N-(4-{[3-(4-methylpiperazin-1-yl)propanoyl]amino}phenyl)-3,4-dihydroisoqu-
inoline-2(1H)-carboxamide; [0745]
N-{4-[(cyclopentylacetyl)amino]phenyl}-5-[(methylsulfonyl)amino]-3,4-dihy-
droisoquinoline-2(1H)-carboxamide; and pharmaceutically acceptable
salts thereof.
Embodiments of Formula (V)
[0746] In another aspect, the present invention provides compounds
of Formula (V)
##STR00010##
and pharmaceutically acceptable salts thereof; wherein X.sup.1,
X.sup.2, X.sup.3, and R.sup.5 are as described herein for Formula
(I).
[0747] In one embodiment of Formula (V), X.sup.1, X.sup.2 and
X.sup.3 are CH; or X.sup.1 and X.sup.3 are CH and X.sup.2 is N; or
X.sup.2 and X.sup.3 are CH and X.sup.1 is N; or X.sup.1 is CR.sup.1
and X.sup.2 and X.sup.3 are CH; or X.sup.2 is CR.sup.1 and X.sup.1
and X.sup.3 are CH; or X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2
are CH.
[0748] In another embodiment of Formula (V), X.sup.1, X.sup.2 and
X.sup.3 are CH. In another embodiment of Formula (V), X.sup.1 and
X.sup.3 are CH and X.sup.2 is N. In another embodiment of Formula
(V), X.sup.2 and X.sup.3 are CH and X.sup.1 is N. In another
embodiment of Formula (V), X.sup.1 is CR.sup.1 and X.sup.2 and
X.sup.3 are CH. In another embodiment of Formula (V), X.sup.2 is
CR.sup.1 and X.sup.1 and X.sup.3 are CH. In another embodiment of
Formula (V), X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are
CH.
[0749] In one embodiment of Formula (V), R.sup.1 is
NHSO.sub.2R.sup.3, F, Cl, Br, or I. In another embodiment of
Formula (V), R.sup.1 is F. In another embodiment of Formula (V),
R.sup.1 is NHSO.sub.2R.sup.3; and R.sup.3 is alkyl.
[0750] In one embodiment of Formula (V), X.sup.1 is CR.sup.1;
X.sup.2 and X.sup.3 are CH; and R.sup.1 is F. In one embodiment of
Formula (V), X.sup.2 is CR.sup.1; X.sup.1 and X.sup.3 are CH; and
R.sup.1 is F. In another embodiment of Formula (V), X.sup.3 is
CR.sup.1; and X.sup.1 and X.sup.2 are CH; and R.sup.1 is
NHSO.sub.2R.sup.3; and R.sup.3 is alkyl.
[0751] In one embodiment of Formula (V),
[0752] X.sup.1 and X.sup.2 and X.sup.3 are CH; or
[0753] X.sup.1 and X.sup.3 are CH; and X.sup.2 is N; or
[0754] X.sup.2 and X.sup.3 are H; and X.sup.1 is N; or
[0755] X.sup.1 is CR.sup.1; and X.sup.2 and X.sup.3 are CH; or
[0756] X.sup.2 is CR.sup.1; and X.sup.1 and X.sup.3 are CH; or
[0757] X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are CH;
[0758] R.sup.1 is NHSO.sub.2R.sup.3, F, Cl, Br, or I;
[0759] R.sup.3 is alkyl;
[0760] R.sup.5 is alkyl, alkenyl, aryl, heterocyclyl, or
cycloalkyl; wherein each alkyl and alkenyl, is optionally
substituted with one or more independently selected R.sup.9,
OR.sup.9, SR.sup.9, SO.sub.2R.sup.9, C(O)R.sup.9, N(R.sup.9).sub.2,
NHC(O)R.sup.9, C(O)NHR.sup.9, OH, or CF.sub.3, F, Cl, Br or I;
[0761] R.sup.9 is alkyl, aryl, heterocyclyl, or cycloalkyl; wherein
each alkyl is optionally substituted with one or more independently
selected OCH.sub.3, aryl, or heterocyclyl;
[0762] wherein the cyclic moieties represented by R.sup.5 and
R.sup.9 are optionally substituted with one or more independently
selected R.sup.13, OR.sup.13, SO.sub.2R.sup.13, C(O)R.sup.13,
CO(O)R.sup.13, NH.sub.2, (O)NHR.sup.13, F, Cl, Br or I;
[0763] R.sup.13 is alkyl, aryl, or heterocyclyl; wherein each alkyl
is optionally substituted with one or more independently selected
R.sup.14, OH, F, Cl, Br or I; and
[0764] R.sup.14 is aryl F, Cl, Br or I.
[0765] Still another embodiment pertains to compounds having
Formula (V), which include [0766]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0767]
N-(4-{[4-(pyridin-2-yl)piperazin-1-yl]carbonyl}phenyl)-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0768]
6-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0769]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1-
H)-carboxamide; [0770]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,6-naphthyridine-2(1H-
)-carboxamide; [0771]
6-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0772]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-car-
boxamide; [0773]
N-[4-(benzylcarbamoyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide;
[0774]
N-(4-{[1-(3-methylbutyl)-1H-pyrazol-4-yl]carbamoyl}phenyl)-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide; [0775]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,6-naphthyridine-
-2(1H)-carboxamide; [0776]
6-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0777]
N-{4-[(1-benzyl-1H-pyrazol-4-yl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-
-2(1H)-carboxamide; [0778]
N-{4-[(2-phenylethyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carb-
oxamide; [0779]
7-fluoro-N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide; [0780]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-
-carboxamide; [0781]
7-fluoro-N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline--
2(1H)-carboxamide; [0782]
7-fluoro-N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide; [0783]
N-{4-[(3-phenylpropyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1-
H)-carboxamide; [0784]
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydro-2,7-naphthyridine-2(1H-
)-carboxamide; [0785]
N-(4-{[2-(2-thienyl)ethyl]carbamoyl}phenyl)-3,4-dihydro-2,7-naphthyridine-
-2(1H)-carboxamide; and pharmaceutically acceptable salts
thereof.
Embodiments of Formula (VI)
[0786] In another aspect, the present invention provides compounds
of Formula (VI)
##STR00011##
and pharmaceutically acceptable salts thereof; wherein X.sup.1,
X.sup.2, and X.sup.3, are as described herein for Formula (I),
R.sup.y is as described for suitable substituents on R.sup.5, and
indicates a single or a double bond.
[0787] In one embodiment of Formula (VI), X.sup.1, X.sup.2 and
X.sup.3 are CH; or X.sup.1 and X.sup.3 are CH and X.sup.2 is N; or
X.sup.2 and X.sup.3 are CH and X.sup.1 is N; or X.sup.1 is CR.sup.1
and X.sup.2 and X.sup.3 are CH; or X.sup.2 is CR.sup.1 and X.sup.1
and X.sup.3 are CH; or X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2
are CH.
[0788] In another embodiment of Formula (VI), X.sup.1, X.sup.2 and
X.sup.3 are CH. In another embodiment of Formula (VI), X.sup.1 and
X.sup.3 are CH and X.sup.2 is N. In another embodiment of Formula
(VI), X.sup.2 and X.sup.3 are CH and X.sup.1 is N. In another
embodiment of Formula (VI), X.sup.1 is CR.sup.1 and X.sup.2 and
X.sup.3 are CH. In another embodiment of Formula (VI), X.sup.2 is
CR.sup.1 and X.sup.1 and X.sup.3 are CH. In another embodiment of
Formula (VI), X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are
CH.
[0789] In one embodiment of Formula (VI), R.sup.1 is
NHSO.sub.2R.sup.3, F, Cl, Br, or I. In another embodiment of
Formula (VI), R.sup.1 is F. In another embodiment of Formula (VI),
R.sup.1 is NHSO.sub.2R.sup.3; and R.sup.3 is alkyl.
[0790] In one embodiment of Formula (VI), X.sup.1 is CR.sup.1;
X.sup.2 and X.sup.3 are CH; and R.sup.1 is F. In one embodiment of
Formula (VI), X.sup.2 is CR.sup.1; X.sup.1 and X.sup.3 are CH; and
R.sup.1 is F. In another embodiment of Formula (VI), X.sup.3 is
CR.sup.1; and X.sup.1 and X.sup.2 are CH; and R.sup.1 is
NHSO.sub.2R.sup.3; and R.sup.3 is alkyl.
[0791] In one embodiment of Formula (VI), is a single bond. In
another embodiment of Formula (VI), is a double bond.
[0792] In one embodiment of Formula (VI),
[0793] X.sup.1 and X.sup.2 and X.sup.3 are CH; or
[0794] X.sup.1 and X.sup.3 are CH; and X.sup.2 is N; or
[0795] X.sup.2 and X.sup.3 are H; and X.sup.1 is N; or
[0796] X.sup.1 is CR.sup.1; and X.sup.2 and X.sup.3 are CH; or
[0797] X.sup.2 is CR.sup.1; and X.sup.1 and X.sup.3 are CH; or
[0798] X.sup.3 is CR.sup.1; and X.sup.1 and X.sup.2 are CH;
[0799] R.sup.1 is NHSO.sub.2R.sup.3, F, Cl, Br, or I;
[0800] R.sup.3 is alkyl;
[0801] R.sup.y is R.sup.13, OR.sup.13, SO.sub.2R.sup.13,
C(O)R.sup.13, CO(O)R.sup.13, NH.sub.2, or C(O)NHR.sup.13;
[0802] R.sup.13 is alkyl, aryl, or heterocyclyl; wherein each alkyl
is optionally substituted with one or more independently selected
R.sup.14, OH, F, Cl, Br or I; and
[0803] R.sup.14 is aryl F, Cl, Br or I.
[0804] Still another embodiment pertains to compounds having
Formula (VI), which include [0805]
N-[4-(1-benzoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0806]
N-[4-(1-butyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquin-
oline-2(1H)-carboxamide; [0807]
N-{4-[1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-di-
hydroisoquinoline-2(1H)-carboxamide; [0808]
N-[4-(1-isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoq-
uinoline-2(1H)-carboxamide; [0809]
N-{4-[1-(3-methylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide; [0810]
N-{4-[1-(methylcarbamoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihy-
droisoquinoline-2(1H)-carboxamide; [0811] tert-butyl
4-{4-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]phenyl}-3,6-dihydrop-
yridine-1(2H)-carboxylate; [0812]
N-[4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0813]
N-{4-[1-(isobutylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide; [0814]
N-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide; [0815]
N-{4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide; [0816]
N-{4-[1-(3-methylbutyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydr-
oisoquinoline-2(1H)-carboxamide; and pharmaceutically acceptable
salts thereof.
Pharmaceutical Compositions, Combination Therapies, Methods of
Treatment, and Administration
[0817] Another embodiment comprises pharmaceutical compositions
comprising a compound having Formula (I) and an excipient.
[0818] Still another embodiment comprises methods of treating
cancer in a mammal comprising administering thereto a
therapeutically acceptable amount of a compound having Formula
(I).
[0819] Still another embodiment pertains to compositions for
treating diseases during which NAMPT is expressed, said
compositions comprising an excipient and a therapeutically
effective amount of the compound having Formula (I).
[0820] Still another embodiment pertains to methods of treating
disease in a patient during which NAMPT is expressed, said methods
comprising administering to the patient a therapeutically effective
amount of a compound having Formula (I).
[0821] Still another embodiment pertains to compositions for
treating inflammatory and tissue repair disorders; particularly
rheumatoid arthritis, inflammatory bowel disease, asthma and COPD
(chronic obstructive pulmonary disease), osteoarthritis,
osteoporosis and fibrotic diseases; dermatosis, including
psoriasis, atopic dermatitis and ultra-violet induced skin damage;
autoimmune diseases including systemic lupus erythematosis,
multiple sclerosis, psoriatic arthritis, ankylosing spondylitis,
tissue and organ rejection, Alzheimer's disease, stroke,
athersclerosis, restenosis, diabetes, glomerulonephritis, cancer,
particularly wherein the cancer is selected from breast, prostate,
lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia,
lymphoma or Hodgkin's disease, cachexia, inflammation associated
with infection and certain viral infections, including Acquired
Immune Deficiency Syndrome (AIDS), adult respiratory distress
syndrome, and ataxia telengiectasia, said compositions comprising
an excipient and a therapeutically effective amount of the compound
having Formula (I).
[0822] Still another embodiment pertains to methods of treating
inflammatory and tissue repair disorders; particularly rheumatoid
arthritis, inflammatory bowel disease, asthma and COPD (chronic
obstructive pulmonary disease), osteoarthritis, osteoporosis and
fibrotic diseases; dermatosis, including psoriasis, atopic
dermatitis and ultra-violet induced skin damage; autoimmune
diseases including systemic lupus erythematosis, multiple
sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and
organ rejection, Alzheimer's disease, stroke, athersclerosis,
restenosis, diabetes, glomerulonephritis, cancer, particularly
wherein the cancer is selected from breast, prostate, lung, colon,
cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or
Hodgkin's disease, cachexia, inflammation associated with infection
and certain viral infections, including Acquired Immune Deficiency
Syndrome (AIDS), adult respiratory distress syndrome, and ataxia
telengiectasia in a patient, said methods comprising administering
to the patient a therapeutically effective amount of a compound
having Formula (I).
[0823] Still another embodiment pertains to compositions for
treating diseases during which NAMPT is expressed, said
compositions comprising an excipient and a therapeutically
effective amount of the compound having Formula (I) and a
therapeutically effective amount of one additional therapeutic
agent or more than one additional therapeutic agent.
[0824] Still another embodiment pertains to methods of treating
disease in a patient during which NAMPT is expressed, said methods
comprising administering to the patient a therapeutically effective
amount of a compound having Formula (I) and a therapeutically
effective amount of one additional therapeutic agent or more than
one additional therapeutic agent.
[0825] Still another embodiment pertains to compositions for
treating inflammatory and tissue repair disorders; particularly
rheumatoid arthritis, inflammatory bowel disease, asthma and COPD
(chronic obstructive pulmonary disease), osteoarthritis,
osteoporosis and fibrotic diseases; dermatosis, including
psoriasis, atopic dermatitis and ultra-violet induced skin damage;
autoimmune diseases including systemic lupus erythematosis,
multiple sclerosis, psoriatic arthritis, ankylosing spondylitis,
tissue and organ rejection, Alzheimer's disease, stroke,
athersclerosis, restenosis, diabetes, glomerulonephritis, cancer,
particularly wherein the cancer is selected from breast, prostate,
lung, colon, cervix, ovary, skin, CNS, bladder, pancreas, leukemia,
lymphoma or Hodgkin's disease, cachexia, inflammation associated
with infection and certain viral infections, including Acquired
Immune Deficiency Syndrome (AIDS), adult respiratory distress
syndrome, and ataxia telengiectasia, said compositions comprising
an excipient and a therapeutically effective amount of the compound
having Formula (I) and a therapeutically effective amount of one
additional therapeutic agent or more than one additional
therapeutic agent.
[0826] Still another embodiment pertains to methods of treating
inflammatory and tissue repair disorders; particularly rheumatoid
arthritis, inflammatory bowel disease, asthma and COPD (chronic
obstructive pulmonary disease), osteoarthritis, osteoporosis and
fibrotic diseases; dermatosis, including psoriasis, atopic
dermatitis and ultra-violet induced skin damage; autoimmune
diseases including systemic lupus erythematosis, multiple
sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and
organ rejection, Alzheimer's disease, stroke, athersclerosis,
restenosis, diabetes, glomerulonephritis, cancer, particularly
wherein the cancer is selected from breast, prostate, lung, colon,
cervix, ovary, skin, CNS, bladder, pancreas, leukemia, lymphoma or
Hodgkin's disease, cachexia, inflammation associated with infection
and certain viral infections, including Acquired Immune Deficiency
Syndrome (AIDS), adult respiratory distress syndrome, and ataxia
telengiectasia in a patient, said methods comprising administering
to the patient a therapeutically effective amount of the compound
having Formula (I) and a therapeutically effective amount of one
additional therapeutic agent or more than one additional
therapeutic agent.
[0827] Metabolites of compounds having Formula (I), produced by in
vitro or in vivo metabolic processes, may also have utility for
treating diseases associated with NAMPT.
[0828] Certain precursor compounds which may be metabolized in
vitro or in vivo to form compounds having Formula (I) may also have
utility for treating diseases associated with NAMPT.
[0829] Compounds having Formula (I) may exist as acid addition
salts, basic addition salts or zwitterions. Salts of the compounds
are prepared during isolation or following purification of the
compounds. Acid addition salts of the compounds are those derived
from the reaction of the compounds with an acid. For example, the
acetate, adipate, alginate, bicarbonate, citrate, aspartate,
benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, formate, fumarate, glycerophosphate,
glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride,
hydrobromide, hydroiodide, lactobionate, lactate, maleate,
mesitylenesulfonate, methanesulfonate, naphthylenesulfonate,
nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate,
picrate, propionate, succinate, tartrate, thiocyanate,
trichloroacetic, trifluoroacetic, para-toluenesulfonate, and
undecanoate salts of the compounds are contemplated as being
embraced by this invention. Basic addition salts of the compounds
are those derived from the reaction of the compounds with the
hydroxide, carbonate or bicarbonate of cations such as lithium,
sodium, potassium, calcium, and magnesium.
[0830] The compounds having Formula (I) may be administered, for
example, bucally, ophthalmically, orally, osmotically, parenterally
(intramuscularly, intraperitoneally intrasternally, intravenously,
subcutaneously), rectally, topically, transdermally or
vaginally.
[0831] Therapeutically effective amounts of compounds having
Formula (I) depend on the recipient of the treatment, the disorder
being treated and the severity thereof, the composition containing
the compound, the time of administration, the route of
administration, the duration of treatment, the compound potency,
its rate of clearance and whether or not another drug is
co-administered. The amount of a compound of this invention having
Formula (I) used to make a composition to be administered daily to
a patient in a single dose or in divided doses is from about 0.03
to about 200 mg/kg body weight. Single dose compositions contain
these amounts or a combination of submultiples thereof.
[0832] Compounds having Formula (I) may be administered with or
without an excipient. Excipients include, for example,
encapsulating materials or additives such as absorption
accelerators, antioxidants, binders, buffers, coating agents,
coloring agents, diluents, disintegrating agents, emulsifiers,
extenders, fillers, flavoring agents, humectants, lubricants,
perfumes, preservatives, propellants, releasing agents, sterilizing
agents, sweeteners, solubilizers, wetting agents and mixtures
thereof.
[0833] Excipients for preparation of compositions comprising a
compound having Formula (I) to be administered orally in solid
dosage form include, for example, agar, alginic acid, aluminum
hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol,
carbomers, castor oil, cellulose, cellulose acetate, cocoa butter,
corn starch, corn oil, cottonseed oil, cross-povidone,
diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl
oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol,
groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic
saline, lactose, magnesium hydroxide, magnesium stearate, malt,
mannitol, monoglycerides, olive oil, peanut oil, potassium
phosphate salts, potato starch, povidone, propylene glycol,
Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl
cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium
sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose,
surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol,
triglycerides, water, and mixtures thereof. Excipients for
preparation of compositions comprising a compound of this invention
having Formula (I) to be administered ophthalmically or orally in
liquid dosage forms include, for example, 1,3-butylene glycol,
castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of
sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive
oil, polyethylene glycols, propylene glycol, sesame oil, water and
mixtures thereof. Excipients for preparation of compositions
comprising a compound of this invention having Formula (I) to be
administered osmotically include, for example,
chlorofluorohydrocarbons, ethanol, water and mixtures thereof.
Excipients for preparation of compositions comprising a compound of
this invention having Formula (I) to be administered parenterally
include, for example, 1,3-butanediol, castor oil, corn oil,
cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic
acid, olive oil, peanut oil, Ringer's solution, safflower oil,
sesame oil, soybean oil, U.S.P. or isotonic sodium chloride
solution, water and mixtures thereof. Excipients for preparation of
compositions comprising a compound of this invention having Formula
(I) to be administered rectally or vaginally include, for example,
cocoa butter, polyethylene glycol, wax and mixtures thereof.
[0834] Compounds having Formula (I) are expected to be useful when
used with alkylating agents, angiogenesis inhibitors, antibodies,
antimetabolites, antimitotics, antiproliferatives, antivirals,
aurora kinase inhibitors, apoptosis promoters (for example, Bcl-xL,
Bcl-w and Bfl-1) inhibitors, activators of death receptor pathway,
Bcr-Abl kinase inhibitors, BiTE (Bi-Specific T cell Engager)
antibodies, antibody drug conjugates, biologic response modifiers,
cyclin-dependent kinase inhibitors, cell cycle inhibitors,
cyclooxygenase-2 inhibitors, DVDs, leukemia viral oncogene homolog
(ErbB2) receptor inhibitors, growth factor inhibitors, heat shock
protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors,
hormonal therapies, immunologicals, inhibitors of inhibitors of
apoptosis proteins (IAPs), intercalating antibiotics, kinase
inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target
of rapamycin inhibitors, microRNA's, mitogen-activated
extracellular signal-regulated kinase inhibitors, multivalent
binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs),
poly ADP (adenosine diphosphate)-ribose polymerase (PARP)
inhibitors, platinum chemotherapeutics, polo-like kinase (Plk)
inhibitors, phosphoinositide-3 kinase (PI3K) inhibitors, proteosome
inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine
kinase inhibitors, retinoids/deltoids plant alkaloids, small
inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors,
ubiquitin ligase inhibitors, and the like, and in combination with
one or more of these agents.
[0835] BiTE antibodies are bi-specific antibodies that direct
T-cells to attack cancer cells by simultaneously binding the two
cells. The T-cell then attacks the target cancer cell. Examples of
BiTE antibodies include adecatumumab (Micromet MT201), blinatumomab
(Micromet MT103) and the like. Without being limited by theory, one
of the mechanisms by which T-cells elicit apoptosis of the target
cancer cell is by exocytosis of cytolytic granule components, which
include perforin and granzyme B. In this regard, Bcl-2 has been
shown to attenuate the induction of apoptosis by both perforin and
granzyme B. These data suggest that inhibition of Bcl-2 could
enhance the cytotoxic effects elicited by T-cells when targeted to
cancer cells (V. R. Sutton, D. L. Vaux and J. A. Trapani, J. of
Immunology 1997, 158 (12), 5783).
[0836] SiRNAs are molecules having endogenous RNA bases or
chemically modified nucleotides. The modifications do not abolish
cellular activity, but rather impart increased stability and/or
increased cellular potency. Examples of chemical modifications
include phosphorothioate groups, 2'-deoxynucleotide,
2'-OCH.sub.3-containing ribonucleotides, 2'-F-ribonucleotides,
2'-methoxyethyl ribonucleotides, combinations thereof and the like.
The siRNA can have varying lengths (e.g., 10-200 bps) and
structures (e.g., hairpins, single/double strands, bulges,
nicks/gaps, mismatches) and are processed in cells to provide
active gene silencing. A double-stranded siRNA (dsRNA) can have the
same number of nucleotides on each strand (blunt ends) or
asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be
present on the sense and/or the antisense strand, as well as
present on the 5'- and/or the 3'-ends of a given strand.
[0837] Multivalent binding proteins are binding proteins comprising
two or more antigen binding sites. Multivalent binding proteins are
engineered to have the three or more antigen binding sites and are
generally not naturally occurring antibodies. The term
"multispecific binding protein" means a binding protein capable of
binding two or more related or unrelated targets. Dual variable
domain (DVD) binding proteins are tetravalent or multivalent
binding proteins binding proteins comprising two or more antigen
binding sites. Such DVDs may be monospecific (i.e., capable of
binding one antigen) or multispecific (i.e., capable of binding two
or more antigens). DVD binding proteins comprising two heavy chain
DVD polypeptides and two light chain DVD polypeptides are referred
to as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVD
polypeptide, a light chain DVD polypeptide, and two antigen binding
sites. Each binding site comprises a heavy chain variable domain
and a light chain variable domain with a total of 6 CDRs involved
in antigen binding per antigen binding site.
[0838] Alkylating agents include altretamine, AMD-473, AP-5280,
apaziquone, bendamustine, brostallicin, busulfan, carboquone,
carmustine (BCNU), chlorambucil, CLORETAZINE.RTM. (laromustine, VNP
40101M), cyclophosphamide, decarbazine, estramustine, fotemustine,
glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide,
melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard
N-oxide, ranimustine, temozolomide, thiotepa, TREANDA.RTM.
(bendamustine), treosulfan, trofosfamide and the like.
[0839] Angiogenesis inhibitors include endothelial-specific
receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth
factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor
(IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors,
matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived
growth factor receptor (PDGFR) inhibitors, thrombospondin analogs,
vascular endothelial growth factor receptor tyrosine kinase (VEGFR)
inhibitors and the like.
[0840] Antimetabolites include ALIMTA.RTM. (pemetrexed disodium,
LY231514, MTA), 5-azacitidine, XELODA.RTM. (capecitabine),
carmofur, LEUSTAT.RTM. (cladribine), clofarabine, cytarabine,
cytarabine ocfosfate, cytosine arabinoside, decitabine,
deferoxamine, doxifluridine, eflornithine, EICAR
(5-ethynyl-1-.beta.-D-ribofuranosylimidazole-4-carboxamide),
enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or
in combination with leucovorin, GEMZAR.RTM. (gemcitabine),
hydroxyurea, ALKERAN.RTM. (melphalan), mercaptopurine,
6-mercaptopurine riboside, methotrexate, mycophenolic acid,
nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,
raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,
tegafur, TS-1, vidarabine, UFT and the like.
[0841] Antivirals include ritonavir, hydroxychloroquine and the
like.
[0842] Aurora kinase inhibitors include ABT-348, AZD-1152,
MLN-8054, VX-680, Aurora A-specific kinase inhibitors, Aurora
B-specific kinase inhibitors and pan-Aurora kinase inhibitors and
the like.
[0843] Bcl-2 protein inhibitors include AT-101 ((-)gossypol),
GENASENSE.RTM. (G3139 or oblimersen (Bcl-2-targeting antisense
oligonucleotide)), IPI-194, IPI-565,
N-(4-(4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4--
(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobe-
nzenesulfonamide) (ABT-737),
N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)pip-
erazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl-
)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide
(ABT-263), GX-070 (obatoclax) and the like.
[0844] Bcr-Abl kinase inhibitors include DASATINIB.RTM.
(BMS-354825), GLEEVEC.RTM. (imatinib) and the like.
[0845] CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387,
CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509,
seliciclib (CYC-202, R-roscovitine), ZK-304709 and the like.
[0846] COX-2 inhibitors include ABT-963, ARCOXIA.RTM. (etoricoxib),
BEXTRA.RTM. (valdecoxib), BMS347070, CELEBREX.RTM. (celecoxib),
COX-189 (lumiracoxib), CT-3, DERAMAXX.RTM. (deracoxib), JTE-522,
4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole),
MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125,
SD-8381, SVT-2016, S-2474, T-614, VIOXX.RTM. (rofecoxib) and the
like.
[0847] EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes,
EGF-vaccine, EMD-7200, ERBITUX.RTM. (cetuximab), HR3, IgA
antibodies, IRESSA.RTM. (gefitinib), TARCEVA.RTM. (erlotinib or
OSI-774), TP-38, EGFR fusion protein, TYKERB.RTM. (lapatinib) and
the like.
[0848] ErbB2 receptor inhibitors include CP-724-714, CI-1033
(canertinib), HERCEPTIN.RTM. (trastuzumab), TYKERB.RTM.
(lapatinib), OMNITARG.RTM. (2C4, petuzumab), TAK-165, GW-572016
(ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine),
APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody,
B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB
AR-209, mAB 2B-1 and the like.
[0849] Histone deacetylase inhibitors include depsipeptide,
LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA),
TSA, valproic acid and the like.
[0850] HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101,
CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953,
MYCOGRAB.RTM. (human recombinant antibody to HSP-90), NCS-683664,
PU24FCl, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the
like.
[0851] Inhibitors of inhibitors of apoptosis proteins include
HGS1029, GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.
[0852] Antibody drug conjugates include anti-CD22-MC-MMAF,
anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC,
MEDI-547, SGN-19 Am SGN-35, SGN-75 and the like
[0853] Activators of death receptor pathway include TRAIL,
antibodies or other agents that target TRAIL or death receptors
(e.g., DR4 and DR5) such as Apomab, conatumumab, ETR2-ST01, GDC0145
(lexatumumab), HGS-1029, LBY-135, PRO-1762 and trastuzumab.
[0854] Kinesin inhibitors include Eg5 inhibitors such as AZD4877,
ARRY-520; CENPE inhibitors such as GSK923295A and the like.
[0855] JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and
INCB018424 and the like.
[0856] MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901,
PD-98059 and the like.
[0857] mTOR inhibitors include AP-23573, CCI-779, everolimus,
RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1/TORC2
inhibitors, including PI-103, PP242, PP30, Torin 1 and the
like.
[0858] Non-steroidal anti-inflammatory drugs include AMIGESIC.RTM.
(salsalate), DOLOBID.RTM. (diflunisal), MOTRIN.RTM. (ibuprofen),
ORUDIS.RTM. (ketoprofen), RELAFEN.RTM. (nabumetone), FELDENE.RTM.
(piroxicam), ibuprofen cream, ALEVE.RTM. (naproxen) and
NAPROSYN.RTM. (naproxen), VOLTAREN.RTM. (diclofenac), INDOCIN.RTM.
(indomethacin), CLINORIL.RTM. (sulindac), TOLECTIN.RTM. (tolmetin),
LODINE.RTM. (etodolac), TORADOL.RTM. (ketorolac), DAYPRO.RTM.
(oxaprozin) and the like.
[0859] PDGFR inhibitors include C-451, CP-673, CP-868596 and the
like.
[0860] Platinum chemotherapeutics include cisplatin, ELOXATIN.RTM.
(oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN.RTM.
(carboplatin), satraplatin, picoplatin and the like.
[0861] Polo-like kinase inhibitors include BI-2536 and the
like.
[0862] Phosphoinositide-3 kinase (PI3K) inhibitors include
wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658,
PX-866, GDC-0941, BGT226, BEZ235, XL765 and the like.
[0863] Thrombospondin analogs include ABT-510, ABT-567, ABT-898,
TSP-1 and the like.
[0864] VEGFR inhibitors include AVASTIN.RTM. (bevacizumab),
ABT-869, AEE-788, ANGIOZYME.TM. (a ribozyme that inhibits
angiogenesis (Ribozyme Pharmaceuticals (Boulder, Colo.) and Chiron,
(Emeryville, Calif.)), axitinib (AG-13736), AZD-2171, CP-547,632,
IM-862, MACUGEN (pegaptamib), NEXAVAR.RTM. (sorafenib, BAY43-9006),
pazopanib (GW-786034), vatalanib (PTK-787, ZK-222584), SUTENT.RTM.
(sunitinib, SU-11248), VEGF trap, ZACTIMA.TM. (vandetanib, ZD-6474)
and the like.
[0865] Antibiotics include intercalating antibiotics aclarubicin,
actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE.RTM.
(bleomycin), daunorubicin, CAELYX.RTM. or MYOCET.RTM. (liposomal
doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS.RTM.
(idarubicin), mitomycin C, nemorubicin, neocarzinostatin,
peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin,
VALSTAR.RTM. (valrubicin), zinostatin and the like.
[0866] Topoisomerase inhibitors include aclarubicin,
9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan,
BN-80915, CAMPTOSAR.RTM. (irinotecan hydrochloride), camptothecin,
CARDIOXANE.RTM. (dexrazoxine), diflomotecan, edotecarin,
ELLENCE.RTM. or PHARMORUBICIN.RTM. (epirubicin), etoposide,
exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,
mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan,
sobuzoxane, SN-38, tafluposide, topotecan and the like.
[0867] Antibodies include AVASTIN.RTM. (bevacizumab), CD40-specific
antibodies, chTNT-1/B, denosumab, ERBITUX.RTM. (cetuximab),
HUMAX-CD4.RTM. (zanolimumab), IGF1R-specific antibodies,
lintuzumab, PANOREX.RTM. (edrecolomab), RENCAREX.RTM. (WX G250),
RITUXAN.RTM. (rituximab), ticilimumab, trastuzimab, CD20 antibodies
types I and II and the like.
[0868] Hormonal therapies include ARIMIDEX.RTM. (anastrozole),
AROMASIN.RTM. (exemestane), arzoxifene, CASODEX.RTM.
(bicalutamide), CETROTIDE.RTM. (cetrorelix), degarelix, deslorelin,
DESOPAN.RTM. (trilostane), dexamethasone, DROGENIL.RTM.
(flutamide), EVISTA.RTM. (raloxifene), AFEMA.TM. (fadrozole),
FARESTON.RTM. (toremifene), FASLODEX.RTM. (fulvestrant),
FEMARA.RTM. (letrozole), formestane, glucocorticoids, HECTOROL.RTM.
(doxercalciferol), RENAGEL.RTM. (sevelamer carbonate),
lasofoxifene, leuprolide acetate, MEGACE.RTM. (megesterol),
MIFEPREX.RTM. (mifepristone), NILANDRON.TM. (nilutamide),
NOLVADEX.RTM. (tamoxifen citrate), PLENAXIS.TM. (abarelix),
prednisone, PROPECIA.RTM. (finasteride), rilostane, SUPREFACT.RTM.
(buserelin), TRELSTAR.RTM. (luteinizing hormone releasing hormone
(LHRH)), VANTAS.RTM. (Histrelin implant), VETORYL.RTM. (trilostane
or modrastane), ZOLADEX.RTM. (fosrelin, goserelin) and the
like.
[0869] Deltoids and retinoids include seocalcitol (EB1089, CB1093),
lexacalcitrol (KH1060), fenretinide, PANRETIN.RTM. (aliretinoin),
ATRAGEN.RTM. (liposomal tretinoin), TARGRETIN.RTM. (bexarotene),
LGD-1550 and the like.
[0870] PARP inhibitors include ABT-888 (veliparib), olaparib,
KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231
and the like.
[0871] Plant alkaloids include, but are not limited to,
vincristine, vinblastine, vindesine, vinorelbine and the like.
[0872] Proteasome inhibitors include VELCADE.RTM. (bortezomib),
MG132, NPI-0052, PR-171 and the like.
[0873] Examples of immunologicals include interferons and other
immune-enhancing agents. Interferons include interferon alpha,
interferon alpha-2a, interferon alpha-2b, interferon beta,
interferon gamma-1a, ACTIMMUNE.RTM. (interferon gamma-1b) or
interferon gamma-n1, combinations thereof and the like. Other
agents include ALFAFERONE.RTM., (IFN-.alpha.), BAM-002 (oxidized
glutathione), BEROMUN.RTM. (tasonermin), BEXXAR.RTM. (tositumomab),
CAMPATH.RTM. (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4),
decarbazine, denileukin, epratuzumab, GRANOCYTE.RTM. (lenograstim),
lentinan, leukocyte alpha interferon, imiquimod, MDX-010
(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim,
MYLOTARG.TM. (gemtuzumab ozogamicin), NEUPOGEN.RTM. (filgrastim),
OncoVAC-CL, OVAREX.RTM. (oregovomab), pemtumomab (Y-muHMFG1),
PROVENGE.RTM. (sipuleucel-T), sargaramostim, sizofilan, teceleukin,
THERACYS.RTM. (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN.RTM.
(immunotherapeutic, Lorus Pharmaceuticals), Z-100 (Specific
Substance of Maruyama (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)),
PROLEUKIN.RTM. (aldesleukin), ZADAXIN.RTM. (thymalfasin),
ZENAPAX.RTM. (daclizumab), ZEVALIN.RTM. (90Y-Ibritumomab tiuxetan)
and the like.
[0874] Biological response modifiers are agents that modify defense
mechanisms of living organisms or biological responses, such as
survival, growth or differentiation of tissue cells to direct them
to have anti-tumor activity and include krestin, lentinan,
sizofuran, picibanil PF-3512676 (CpG-8954), ubenimex and the
like.
[0875] Pyrimidine analogs include cytarabine (ara C or Arabinoside
C), cytosine arabinoside, doxifluridine, FLUDARA.RTM.
(fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR.RTM.
(gemcitabine), TOMUDEX.RTM. (ratitrexed), TROXATYL.TM.
(triacetyluridine troxacitabine) and the like.
[0876] Purine analogs include LANVIS.RTM. (thioguanine) and
PURI-NETHOL.RTM. (mercaptopurine).
[0877] Antimitotic agents include batabulin, epothilone D
(KOS-862),
N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,
ixabepilone (BMS 247550), paclitaxel, TAXOTERE.RTM. (docetaxel),
PNU100940 (109881), patupilone, XRP-9881 (larotaxel), vinflunine,
ZK-EPO (synthetic epothilone) and the like.
[0878] Ubiquitin ligase inhibitors include MDM2 inhibitors, such as
nutlins, NEDD8 inhibitors such as MLN4924 and the like.
[0879] Compounds of this invention can also be used as
radiosensitizers that enhance the efficacy of radiotherapy.
Examples of radiotherapy include external beam radiotherapy,
teletherapy, brachytherapy and sealed, unsealed source radiotherapy
and the like.
[0880] Additionally, compounds having Formula (I) may be combined
with other chemotherapeutic agents such as ABRAXANE.TM. (ABI-007),
ABT-100 (farnesyl transferase inhibitor), ADVEXIN.RTM. (Ad5CMV-p53
vaccine), ALTOCOR.RTM. or MEVACOR.RTM. (lovastatin), AMPLIGEN.RTM.
(poly I:poly C12U, a synthetic RNA), APTOSYN.RTM. (exisulind),
AREDIA.RTM. (pamidronic acid), arglabin, L-asparaginase, atamestane
(1-methyl-3,17-dione-androsta-1,4-diene), AVAGE.RTM. (tazarotene),
AVE-8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or
cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC.RTM.
(cancer vaccine), CELEUK.RTM. (celmoleukin), CEPLENE.RTM.
(histamine dihydrochloride), CERVARIX.RTM. (human papillomavirus
vaccine), CHOP.RTM. (C: CYTOXAN.RTM. (cyclophosphamide); H:
ADRIAMYCIN.RTM. (hydroxydoxorubicin); O: Vincristine
(ONCOVIN.RTM.); P: prednisone), CYPAT.TM. (cyproterone acetate),
combrestatin A4P, DAB(389)EGF (catalytic and translocation domains
of diphtheria toxin fused via a His-Ala linker to human epidermal
growth factor) or TransMID-107R.TM. (diphtheria toxins),
dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid
(DMXAA), eniluracil, EVIZON.TM. (squalamine lactate),
DIMERICINE.RTM. (T4N5 liposome lotion), discodermolide, DX-8951f
(exatecan mesylate), enzastaurin, EPO906 (epithilone B),
GARDASIL.RTM. (quadrivalent human papillomavirus (Types 6, 11, 16,
18) recombinant vaccine), GASTRIMMUNE.RTM., GENASENSE.RTM., GMK
(ganglioside conjugate vaccine), GVAX.RTM. (prostate cancer
vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic
acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox),
IL-13-pseudomonas exotoxin, interferon-.alpha., interferon-.gamma.,
JUNOVAN.TM. or MEPACT.TM. (mifamurtide), lonafarnib,
5,10-methylenetetrahydrofolate, miltefosine
(hexadecylphosphocholine), NEOVASTAT.RTM. (AE-941), NEUTREXIN.RTM.
(trimetrexate glucuronate), NIPENT.RTM. (pentostatin),
ONCONASE.RTM. (a ribonuclease enzyme), ONCOPHAGE.RTM. (melanoma
vaccine treatment), ONCOVAX.RTM. (IL-2 Vaccine), ORATHECIN.TM.
(rubitecan), OSIDEM.RTM. (antibody-based cell drug), OVAREX.RTM.
MAb (murine monoclonal antibody), paclitaxel, PANDIMEX.TM.
(aglycone saponins from ginseng comprising 20(S)protopanaxadiol
(aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab,
PANVAC.RTM.-VF (investigational cancer vaccine), pegaspargase, PEG
Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB.RTM.
(catumaxomab), REVLIMID.RTM. (lenalidomide), RSR13 (efaproxiral),
SOMATULINE.RTM. LA (lanreotide), SORIATANE.RTM. (acitretin),
staurosporine (Streptomyces staurospores), talabostat (PT100),
TARGRETIN.RTM. (bexarotene), TAXOPREXIN.RTM. (DHA-paclitaxel),
TELCYTA.RTM. (canfosfamide, TLK286), temilifene, TEMODAR.RTM.
(temozolomide), tesmilifene, thalidomide, THERATOPE.RTM. (STn-KLH),
thymitaq
(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazoline
dihydrochloride), TNFERADE.TM. (adenovector: DNA carrier containing
the gene for tumor necrosis factor-.alpha.), TRACLEER.RTM. or
ZAVESCA.RTM. (bosentan), tretinoin (Retin-A), tetrandrine,
TRISENOX.RTM. (arsenic trioxide), VIRULIZIN.RTM., ukrain
(derivative of alkaloids from the greater celandine plant), vitaxin
(anti-alphavbeta3 antibody), XCYTRIN.RTM. (motexafin gadolinium),
XINLAY.TM. (atrasentan), XYOTAX.TM. (paclitaxel poliglumex),
YONDELIS.RTM. (trabectedin), ZD-6126, ZINECARD.RTM. (dexrazoxane),
ZOMETA.RTM. (zolendronic acid), zorubicin and the like.
Data
[0881] Determination of the utility of compounds having Formula (I)
as binders to and inhibitors of NAMPT was performed using a
Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET)
binding assay.
Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET)
Binding Assay of NAMPT
[0882] The assay was carried out in 18 uL low volume plates (Owens
Corning) in reaction buffer (50 mM HEPES (NaOH), pH 7.5, 100 mM
NaCl, 10 mM MgCl.sub.2, 1 mM DTT, 1% Glycerol) using 6.8 nM
recombinant, human, C-terminally-His tagged NAMPT, 1 nM Tb-anti-His
antibody (Invitrogen, Cat # PV5895), and 200 nM probe (Oregon Green
488-conjugated APO866; A-1251667.0). Plates were covered, and
reactions were carried out for 2-3 hours. Plates were read with
Envision (Laser Lantha low volume protocol) after 2 to 3 hours.
Excitation was carried out at 337 nm, and the ratio of emission of
Oregon Green (520 nm) to terbium (492 nm) was determined and used
to calculate IC.sub.50 values of test compounds.
[0883] TABLE 1 shows the utility of compounds having Formula Ito
functionally inhibit NAMPT.
TABLE-US-00001 TABLE 1 TR-FRET Binding - IC50 Example (.mu.M) 1
0.0167 2 0.0132 3 0.0138 4 0.015 5 0.0157 6 0.0103 7 0.0207 8
0.0237 9 0.0291 10 0.0294 11 0.0433 12 0.0452 13 0.0458 14 0.0471
15 0.0976 16 0.171 17 0.178 18 0.178 19 0.195 20 0.248 21 0.286 22
0.309 23 0.366 25 0.597 26 0.80 27 1.03 28 1.25 29 1.5 30 2.11 31
0.00616 32 0.012 33 0.0404 34 0.0388 35 0.103 36 0.185 37 0.298 38
0.391 39 0.611 40 0.645 41 0.819 42 1.29 43 0.0101 44 0.0136 45
0.0138 46 0.0153 47 0.0202 48 0.0326 49 0.0487 50 0.0586 51 0.0749
52 0.0805 53 0.112 54 0.289 55 0.435 56 0.189 57 0.887 58 1.26 59
0.864 60 1.37 61 1.25 62 1.47 63 0.0107 64 0.055 65 0.116 66 0.0153
67 0.0167 68 0.00445 69 0.00649 70 0.109 71 0.00275 72 0.0168 73
0.0332 74 0.0862 75 0.196 76 0.0148 77 0.00516 78 0.0663 79 0.0053
80 0.191 81 Nd 82 0.049 83 0.269 84 0.0858 85 0.242 86 0.377 87
0.116 88 0.134 89 0.203 90 0.314 91 0.016 92 5.84 93 0.53 94 0.0692
95 0.158 96 0.128 97 1.49 98 0.003 nd = no data
[0884] Compounds which inhibit NAMPT are useful for treating
diseases in which activation of NF-KB is implicated. Such methods
are useful in the treatment of a variety of diseases including
inflammatory and tissue repair disorders; particularly rheumatoid
arthritis, inflammatory bowel disease, asthma and COPD (chronic
obstructive pulmonary disease), osteoarthritis, osteoporosis and
fibrotic diseases; dermatosis, including psoriasis, atopic
dermatitis and ultra-violet induced skin damage; autoimmune
diseases including systemic lupus erythematosis, multiple
sclerosis, psoriatic arthritis, ankylosing spondylitis, tissue and
organ rejection, Alzheimer's disease, stroke, athersclerosis,
restenosis, diabetes, glomerulonephritis, cancer, particularly
wherein the cancer is selected from breast, prostate, lung, colon,
cervix, ovary, skin, CNS, bladder, pancreas, leukaemia, lymphoma or
Hodgkin's disease, cachexia, inflammation associated with infection
and certain viral infections, including Acquired Immune Deficiency
Syndrome (AIDS), adult respiratory distress syndrome, and ataxia
telengiectasia.
[0885] Involvement of NAMPT in the treatment of cancer is described
in WO 97/48696. Involvement of NAMPT in immuno-supression is
described in WO 97/48397. Involvement of NAMPT for the treatment of
diseases involving angiogenesis is described in WO 2003/80054.
Involvement of NAMPT for the treatment of rheumatoid arthritis and
septic shock is described in WO 2008/025857. Involvement of NAMPT
for the prophlaxis and treatment of ischaemia is described in WO
2009/109610.
[0886] Cancers include, but are not limited to, hematologic and
solid tumor types such as acoustic neuroma, acute leukemia, acute
lymphoblastic leukemia, acute myelogenous leukemia (monocytic,
myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma,
myelomonocytic and promyelocytic), acute t-cell leukemia, basal
cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer,
breast cancer (including estrogen-receptor positive breast cancer),
bronchogenic carcinoma, Burkitt's lymphoma, cervical cancer,
chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,
chronic lymphocytic leukemia, chronic myelocytic (granulocytic)
leukemia, chronic myelogenous leukemia, colon cancer, colorectal
cancer, craniopharyngioma, cystadenocarcinoma, dysproliferative
changes (dysplasias and metaplasias), embryonal carcinoma,
endometrial cancer, endotheliosarcoma, ependymoma, epithelial
carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor
positive breast cancer, essential thrombocythemia, Ewing's tumor,
fibrosarcoma, gastric carcinoma, germ cell testicular cancer,
gestational trophobalstic disease, glioblastoma, head and neck
cancer, heavy chain disease, hemangioblastoma, hepatoma,
hepatocellular cancer, hormone insensitive prostate cancer,
leiomyosarcoma, liposarcoma, lung cancer (including small cell lung
cancer and non-small cell lung cancer),
lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblastic
leukemia, lymphoma (lymphoma, including diffuse large B-cell
lymphoma, follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's
lymphoma), malignancies and hyperproliferative disorders of the
bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and
uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia,
medullary carcinoma, medulloblastoma, melanoma, meningioma,
mesothelioma, multiple myeloma, myelogenous leukemia, myeloma,
myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer,
osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary
adenocarcinomas, papillary carcinoma, peripheral T-cell lymphoma,
pinealoma, polycythemia vera, prostate cancer (including
hormone-insensitive (refractory) prostate cancer), rectal cancer,
renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma,
sebaceous gland carcinoma, seminoma, skin cancer, small cell lung
carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer,
squamous cell carcinoma, synovioma, sweat gland carcinoma,
testicular cancer (including germ cell testicular cancer), thyroid
cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine
cancer, Wilms' tumor and the like.
Schemes and Experimentals
[0887] The following abbreviations have the meanings indicated.
ADDP means 1,1'-(azodicarbonyl)dipiperidine; AD-mix-.beta. means a
mixture of (DHQD).sub.2PHAL, K.sub.3Fe(CN).sub.6, K.sub.2CO.sub.3,
and K.sub.2SO.sub.4; 9-BBN means 9-borabicyclo(3.3.1)nonane; Boc
means tert-butoxycarbonyl; (DHQD).sub.2PHAL means hydroquinidine
1,4-phthalazinediyl diethyl ether; DBU means
1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means diisobutylaluminum
hydride; DIEA means diisopropylethylamine; DMAP means
N,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe
means 1,2-bis(dimethylphosphino)ethane; DMSO means
dimethylsulfoxide; dppb means 1,4-bis(diphenylphosphino)-butane;
dppe means 1,2-bis(diphenylphosphino)ethane; dppf means
1,1'-bis(diphenylphosphino)ferrocene; dppm means
1,1-bis(diphenylphosphino)methane; EDAC.HCl means
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc
means fluorenylmethoxycarbonyl; HATU means
O-(7-azabenzotriazol-1-yl)-N,N'N'N'-tetramethyluronium
hexafluorophosphate; HMPA means hexamethylphosphoramide; IPA means
isopropyl alcohol; MP-BH.sub.3 means macroporous triethylammonium
methylpolystyrene cyanoborohydride; TEA means triethylamine; TFA
means trifluoroacetic acid; THF means tetrahydrofuran; NCS means
N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means
N-methylpyrrolidine; PPh.sub.3 means triphenylphosphine.
[0888] The following schemes are presented to provide what is
believed to be the most useful and readily understood description
of procedures and conceptual aspects of this invention. Compounds
of this invention may be made by synthetic chemical processes,
examples of which are shown herein. It is meant to be understood
that the order of the steps in the processes may be varied, that
reagents, solvents and reaction conditions may be substituted for
those specifically mentioned, and that vulnerable moieties may be
protected and deprotected, as necessary.
Schemes
##STR00012##
[0890] As shown in Scheme 1, compounds of formula (1), wherein
X.sup.1 and X.sup.2 are as described herein, can be reacted with
methyl 4-isocyanatobenzoate to provide compounds of formula (2).
The reaction is typically performed in a solvent such as but not
limited to tetrahydrofuran. The methyl 4-isocyanatobenzoate is
typically added at low temperature followed by stirring at room
temperature. Compounds of formula (3) can be prepared by reacting
compounds of formula (2) with aqueous lithium hydroxide. The
reaction is typically performed in a solvent such as but not
limited to tetrahydrofuran, methanol, or mixtures thereof.
Compounds of formula (3) can be reacted with amine of formula (3A),
wherein each R.sup.5 is hydrogen or is as described herein, using
coupling conditions known to those skilled in the art and readily
available in the literature to provide compounds of formula (4),
which are representative of the compounds of this invention.
##STR00013##
[0891] As shown in Scheme 2, compounds of formula (1), wherein
X.sup.1 and X.sup.2 are as described herein, can be reacted with
4-nitrophenylisocyanate to provide compounds of formula (5). The
reaction is typically performed in a solvent such as but not
limited to tetrahydrofuran. Compounds of formula (5) can be treated
with a hydrogen balloon in the presence of 10% Pd on carbon to
provide compounds of formula (6). The reaction is typically
performed at ambient temperature in a solvent such as but not
limited to dimethylformamide. Compounds of formula (6) can be
reacted with acid of formula (6A), wherein R.sup.5 is as described
herein, using coupling conditions known to those skilled in the art
and readily available in the literature to provide compounds of
formula (7), which are representative of the compounds of this
invention.
##STR00014##
[0892] As shown in Scheme 3, compounds of formula (1), wherein
X.sup.1 and X.sup.2 are as described herein, can be reacted with
4-bromophenyl isocyanate to provide compounds of formula (8). The
reaction is typically performed in a solvent such as but not
limited to tetrahydrofuran. Compounds of formula (8) can be reacted
with a boronic acid of formula (9A) (or an appropriate boronate
ester), wherein R.sup.5 is as described herein, using Suzuki
Coupling conditions known to those skilled in the art and readily
available in the literature to provide compounds of formula (9),
which are representative of the compounds of this invention.
[0893] The following examples are presented to provide what is
believed to be the most useful and readily understood description
of procedures and conceptual aspects of this invention. The
exemplified compounds were named using ACD/ChemSketch Version 12.01
(13 May 2009), Advanced Chemistry Development Inc., Toronto,
Ontario), or ChemDraw.RTM. Ver. 9.0.5 (CambridgeSoft, Cambridge,
Mass.). Intermediates were named using ChemDraw.RTM. Ver. 9.0.5
(CambridgeSoft, Cambridge, Mass.).
EXPERIMENTALS
Example 1
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide
Example 1A
methyl 4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoate
[0894] In a 250 mL round bottom flask was mixed
1,2,3,4-tetrahydroisoquinoline (1.90 ml, 15.02 mmol) in anhydrous
dichloromethane (70 ml) at 0.degree. C. Methyl 4-isocyanatobenzoate
(2.93 g, 16.52 mmol) was added in a single portion and the reaction
was stirred at 0.degree. C. for 2 hours and over the weekend at
room temperature. The solvent was evaporated and the resulting foam
was triturated with ether and filtered to give the title
compound.
Example 1B
4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoic acid
[0895] In a 250 mL round bottom flask was mixed methyl
4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoate (3.43 g,
11.05 mmol) in tetrahydrofuran (40 ml) and methanol (40 ml) at room
temperature. To this solution was added 4N aqueous sodium hydroxide
(13.82 ml, 55.3 mmol) and the solution was stirred at room
temperature for 6 hours. The organic solvents were evaporated and
the aqueous solution was acidified to pH 3 using 3N aqueous HCl.
The resulting suspension was filtered with water washes to give the
title compound after vacuum drying.
Example 1C
N-{4-[(3-methylbutyl)carbamoyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide
[0896] 4-(1,2,3,4-Tetrahydroisoquinoline-2-carboxamido)benzoic acid
(25 mg, 0.084 mmol), 1-hydroxybenzotriazole (19.38 mg, 0.127 mmol)
and diisopropylethylamine (0.044 ml, 0.253 mmol) were dissolved in
dimethylformamide (1 ml) and treated with 3-methylbutan-1-amine
(0.015 ml, 0.127 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (24.26
mg, 0.127 mmol). The homogeneous solution was stirred at ambient
temperature overnight. The mixture was diluted with water,
extracted with ethyl acetate, washed with brine, dried over
MgSO.sub.4, filtered and concentrated. The residue was triturated
with methylene chloride and filtered to provide the title compound.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 8.79 (s, 1H), 8.20
(t, J=5.6 Hz, 1H), 7.70-7.75 (m, 2H), 7.54-7.58 (m, 2H), 7.16-7.22
(m, 4H), 4.64-4.65 (bs, 2H), 3.71 (t, J=5.9 Hz, 2H), 3.25 (q, J=6.7
Hz, 2H), 2.86 (t, J=5.8 Hz, 2H), 1.61 (dp, J=13.3, 6.6 Hz, 1H),
1.37-1.44 (m, 2H), 0.90 (d, J=6.6 Hz, 6H); (ESI(+)) m/e 366
(M+H).sup.+.
TABLE-US-00002 TABLE 2 The following examples were prepared
essentially as described in Example 1, substituting the appropriate
amine for 1,2,3,4-tetrahydroisoquinoline in Example 1A and the
appropriate amine for 3-methylbutan-1-amine in Example 1C. Ex Name
.sup.1H NMR MS 2 N-(4-{[4-(pyridin-2- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.79 (ESI(+)) yl)piperazin-1- (s, 1H),
8.13 (ddd, J = 4.8, 2.0, 0.8 Hz, 1H), m/e 442
yl]carbonyl}phenyl)-3,4- 7.56-7.60 (m, 2H), 7.55 (ddd, J = 8.5,
7.2, (M + H).sup.+ dihydroisoquinoline- 2.0 Hz, 1H), 7.34-7.37 (m,
2H), 7.19-7.20 2(1H)-carboxamide (m, 4H), 6.84 (dt, J = 8.6, 0.9
Hz, 1H), 6.67 (ddd, J = 7.0, 4.9, 0.8 Hz, 1H), 4.65-4.66 (bs, 2H),
3.72 (t, J = 5.9 Hz, 2H), 3.49-3.68 (m, 8H), 2.86 (t, J = 5.8 Hz,
2H) 3 6-fluoro-N-{4-[(3- .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.81 (ESI(-)) phenylpropyl)carbamoyl] (s, 1H), 8.29 (t,
J = 5.5 Hz, 1H), 7.73-7.76 m/e 430 phenyl}-3,4- (m, 2H), 7.55-7.57
(m, 2H), 7.25-7.32 (m, (M - H).sup.- dihydroisoquinoline- 2H),
7.20-7.25 (m, 3H), 7.15-7.20 (m, 1H), 2(1H)-carboxamide 7.02-7.07
(m, 2H), 4.62-4.63 (bs, 2H), 3.70 (t, J = 5.9 Hz, 2H), 3.18-3.27
(m, 2H), 2.87 (t, J = 5.9 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H), 1.82
(p, J = 7.4 Hz, 2H) 4 N-{4-[(3- .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.88 (ESI(+)) phenylpropyl)carbamoyl] (s, 1H), 8.41 (s,
1H), 8.35 (d, J = 5.0 Hz, m/e 415 phenyl}-3,4-dihydro-2,6- 1H),
8.29 (t, J = 5.6 Hz, 1H), 7.74-7.77 (m, (M + H).sup.+
naphthyridine-2(1H)- 2H), 7.54-7.58 (m, 2H), 7.26-7.31 (m, 2H),
carboxamide 7.20-7.25 (m, 3H), 7.15-7.20 (m, 1H), 4.67- 4.68 (bs,
2H), 3.76 (t, J = 5.8 Hz, 2H), 3.22- 3.29 (m, 2H), 2.87 (t, J = 5.7
Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H), 1.82 (p, J = 7.4 Hz, 2H) 5
N-{4-[(3- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.87
(ESI(+)) methylbutyl)carbamoyl] (s, 1H), 8.40 (s, 1H), 8.35 (d, J =
5.0 Hz, m/e 367 phenyl}-3,4-dihydro-2,6- 1H), 8.21 (t, J = 5.6 Hz,
1H), 7.72-7.76 (m, (M + H).sup.+ naphthyridine-2(1H)- 2H),
7.54-7.57 (m, 2H), 7.21 (d, J = 5.1 Hz, carboxamide 1H), 4.67-4.68
(bs, 2H), 3.75 (t, J = 5.7 Hz, 2H), 3.22-3.27 (m, 2H), 2.85-2.89
(m, 2H), 1.54-1.66 (m, 1H), 1.41 (q, J = 7.1 Hz, 2H), 0.87-0.95 (m,
6H) 6 6-fluoro-N-{4-[(3- .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.82 (ESI(+)) methylbutyl)carbamoyl] (s, 1H), 8.22 (t,
J = 5.6 Hz, 1H), 7.72-7.75 m/e 384 phenyl}-3,4- (m, 2H), 7.54-7.57
(m, 2H), 7.19-7.25 (m, (M + H).sup.+ dihydroisoquinoline- 1H),
7.02-7.07 (m, 2H), 4.62-4.63 (bs, 2H), 2(1H)-carboxamide 3.70 (t, J
= 5.8 Hz, 2H), 3.22-3.28 (m, 2H), 2.85-2.89 (m, 2H), 1.54-1.66 (m,
1H), 1.41 (q, J = 7.1 Hz, 2H), 0.90 (d, J = 6.6 Hz, 6H) 7 N-{4-[(3-
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 8.80 (ESI(+))
phenylpropyl)carbamoyl] (s, 1H), 8.28 (t, J = 5.5 Hz, 1H),
7.72-7.77 m/e 414 phenyl}-3,4- (m, 2H), 7.55-7.59 (m, 2H),
7.18-7.29 (m, (M + H).sup.+ dihydroisoquinoline- 9H), 4.65-4.66
(bs, 2H), 3.71 (t, J = 5.8 Hz, 2(1H)-carboxamide 2H), 3.21-3.30 (m,
2H), 2.86 (t, J = 5.8 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H), 1.76-1.87
(m, 2H) 8 N-[4- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
8.85 (ESI(+)) (benzylcarbamoyl)phenyl]- (t, J = 6.0 Hz, 1H),
8.81-8.83 (bs, 1H), 7.79- m/e 386 3,4-dihydroisoquinoline- 7.82 (m,
2H), 7.57-7.60 (m, 2H), 7.29-7.35 (M + H).sup.+ 2(1H)-carboxamide
(m, 4H), 7.20-7.25 (m, 1H), 7.17-7.21 (m, 4H), 4.65-4.66 (bs, 2H),
4.46 (d, J = 5.9 Hz, 2H), 3.71 (t, J = 5.9 Hz, 2H), 2.86 (t, J =
5.8 Hz, 2H) 11 N-(4-{[1-(3- .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm (ESI(+)) methylbutyl)-1H-pyrazol- 10.21 (s, 1H), 8.86
(s, 1H), 8.02 (s, 1H), m/e 432 4-yl]carbamoyl}phenyl)- 7.84-7.87
(m, 2H), 7.62-7.64 (m, 2H), 7.56 (M + H).sup.+
3,4-dihydroisoquinoline- (s, 1H), 7.20 (s, 3H), 7.20 (s, 1H),
4.66-4.67 2(1H)-carboxamide (bs, 2H), 4.09 (t, J = 7.2 Hz, 2H),
3.73 (t, J = 5.9 Hz, 2H), 2.87 (t, J = 5.8 Hz, 2H), 1.65 (q, J =
7.0 Hz, 2H), 1.40-1.55 (m, 1H), 0.90 (d, J = 6.6 Hz, 6H) 12
N-(4-{[2-(2- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.90
(ESI(+)) thienyl)ethyl]carbamoyl} (s, 1H), 8.45 (t, J = 5.3 Hz,
1H), 8.39-8.43 m/e 407 phenyl)-3,4-dihydro-2,6- (bs, 1H), 8.36 (d,
J = 4.9 Hz, 1H), 7.74-7.77 (M + H).sup.+ naphthyridine-2(1H)- (m,
2H), 7.55-7.58 (m, 2H), 7.33 (d, J = 5.0 carboxamide Hz, 1H), 7.22
(d, J = 5.0 Hz, 1H), 6.90-6.97 (m, 2H), 4.67-4.69 (bs, 2H),
3.74-3.78 (m, 2H), 3.42-3.51 (m, 2H), 3.00-3.10 (m, 2H), 2.85-2.89
(m, 2H) 13 6-fluoro-N-(4-{[2-(2- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.83 (ESI(+)) thienyl)ethyl]carbamoyl}
(s, 1H), 8.43-8.47 (m, 1H), 7.73-7.76 (m, m/e 424 phenyl)-3,4- 2H),
7.55-7.58 (m, 2H), 7.33 (d, J = 5.1 Hz, (M + H).sup.+
dihydroisoquinoline- 1H), 7.19-7.27 (m, 1H), 7.01-7.07 (m, 2H),
2(1H)-carboxamide 6.95 (dd, J = 5.0, 3.5 Hz, 1H), 6.91 (d, J = 3.4
Hz, 1H), 4.62-4.63 (bs, 2H), 3.70 (t, J = 5.8 Hz, 2H), 3.42-3.53
(m, 2H), 3.05 (t, J = 7.2 Hz, 2H), 2.85-2.89 (m, 2H) 14
N-{4-[(1-benzyl-1H- .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
(ESI(+)) pyrazol-4- 10.25 (s, 1 H) 8.86 (s, 1 H) 8.11 (s, 1 H) m/e
452 yl)carbamoyl]phenyl}- 7.84 (d, J = 8.9 Hz, 2 H) 7.57-7.67 (m, 3
H) (M + H).sup.+ 3,4-dihydroisoquinoline- 7.16-7.38 (m, 9 H) 5.31
(s, 2 H) 4.66 (s, 2 H) 2(1H)-carboxamide 3.72 (t, J = 6.0 Hz, 2 H)
2.81-2.93 (m, 2 H) 15 N-{4-[(2- .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 8.80 (ESI(+)) phenylethyl)carbamoyl] (s, 1H), 8.38 (t,
J = 5.6 Hz, 1H), 7.72-7.75 m/e 400 phenyl}-3,4- (m, 2H), 7.55-7.58
(m, 2H), 7.27-7.33 (m, (M + H).sup.+ dihydroisoquinoline- 2H),
7.22-7.26 (m, 2H), 7.15-7.22 (m, 5H), 2(1H)-carboxamide 4.65-4.66
(bs, 2H), 3.71 (t, J = 5.9 Hz, 2H), 3.44-3.48 (m, 2H), 2.82-2.87
(m, 4H) 16 7-fluoro-N-{4-[(3- .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.82 (ESI(+)) methylbutyl)carbamoyl] (s, 1H), 8.21 (t,
J = 5.6 Hz, 1H), 7.72-7.75 m/e 384 phenyl}-3,4- (m, 2H), 7.53-7.57
(m, 2H), 7.23 (dd, J = (M + H).sup.+ dihydroisoquinoline- 8.3, 5.8
Hz, 1H), 6.98-7.07 (m, 2H), 4.64- 2(1H)-carboxamide 4.65 (bs, 2H),
3.71 (t, J = 5.8 Hz, 2H), 3.22- 3.27 (m, 2H), 2.81-2.90 (m, 2H),
1.61 (dq, J = 13.3, 6.6 Hz, 1H), 1.41 (q, J = 7.1 Hz, 2H), 0.90 (d,
J = 6.6 Hz, 6H) 17 N-(4-{[2-(2- .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm (ESI(+)) thienyl)ethyl]carbamoyl} 8.92-8.93 (bs, 1H),
8.48-8.52 (m, 1H), 7.74- m/e 406 phenyl)-3,4- 7.77 (m, 2H),
7.59-7.62 (m, 2H), 7.33 (dd, (M + H).sup.+ dihydroisoquinoline- J =
5.0, 1.3 Hz, 1H), 7.19 (s, 4H), 6.95 (dd, 2(1H)-carboxamide J =
5.1, 3.3 Hz, 1H), 6.91 (d, J = 3.3 Hz, 1H), 4.66-4.67 (bs, 2H),
3.73 (t, J = 5.8 Hz, 2H), 3.45-3.51 (m, 2H), 3.05 (t, J = 7.2 Hz,
2H), 2.86 (t, J = 5.8 Hz, 2H) 20 7-fluoro-N-{4-[(3- .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 8.83 (ESI(+))
phenylpropyl)carbamoyl] (s, 1H), 8.29 (t, J = 5.5 Hz, 1H),
7.73-7.76 m/e 432 phenyl}-3,4- (m, 2H), 7.54-7.57 (m, 2H),
7.26-7.31 (m, (M + H).sup.+ dihydroisoquinoline- 2H), 7.20-7.25 (m,
3H), 7.15-7.20 (m, 1H), 2(1H)-carboxamide 6.98-7.07 (m, 2H),
4.64-4.65 (bs, 2H), 3.71 (t, J = 5.8 Hz, 2H), 3.21-3.29 (m, 2H),
2.81- 2.85 (m, 2H), 2.62 (t, J = 7.6 Hz, 2H), 1.82 (p, J = 7.3 Hz,
2H) 23 7-fluoro-N-(4-{[2-(2- .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.84 (ESI(+)) thienyl)ethyl]carbamoyl} (s, 1H), 8.45
(t, J = 5.6 Hz, 1H), 7.73-7.76 m/e 424 phenyl)-3,4- (m, 2H),
7.55-7.58 (m, 2H), 7.33 (dd, J = (M + H).sup.+ dihydroisoquinoline-
5.0, 1.2 Hz, 1H), 7.23 (dd, J = 8.3, 5.8 Hz, 2(1H)-carboxamide 1H),
7.00-7.08 (m, 2H), 6.95 (dd, J = 5.1, 3.4 Hz, 1H), 6.90-6.92 (m,
1H), 4.64-4.65 (bs, 2H), 3.71 (t, J = 5.8 Hz, 2H), 3.45-3.51 (m,
2H), 3.05 (t, J = 7.2 Hz, 2H), 2.82-2.89 (m, 2H) 25 N-{4-[(3-
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 8.88 (ESI(+))
phenylpropyl)carbamoyl] (s, 1H), 8.41 (s, 1H), 8.34 (d, J = 5.0 Hz,
m/e 415 phenyl}-3,4-dihydro-2,7- 1H), 8.29 (t, J = 5.6 Hz, 1H),
7.74-7.76 (m, (M + H).sup.+ naphthyridine-2(1H)- 2H), 7.55-7.57 (m,
2H), 7.27-7.30 (m, 2H), carboxamide 7.21-7.24 (m, 3H), 7.16-7.19
(m, 1H), 4.69- 4.70 (bs, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.26 (q, J
= 6.5 Hz, 2H), 2.87 (t, J = 5.9 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H),
1.82 (p, J = 7.4 Hz, 2H) 28 N-{4-[(3- .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 8.88 (ESI(+)) methylbutyl)carbamoyl] (s,
1H), 8.41 (s, 1H), 8.34 (d, J = 5.0 Hz, m/e 367
phenyl}-3,4-dihydro-2,7- 1H), 8.23 (t, J = 5.6 Hz, 1H), 7.73-7.75
(m, (M + H).sup.+ naphthyridine-2(1H)- 2H), 7.54-7.56 (m, 2H), 7.22
(d, J = 5.0 Hz, carboxamide 1H), 4.69-4.70 (bs, 2H), 3.73 (t, J =
5.9 Hz, 2H), 3.23-3.28 (m, 2H), 2.88 (t, J = 5.9 Hz, 2H), 1.61 (dq,
J = 13.3, 6.7 Hz, 1H), 1.41 (q, J = 7.1 Hz, 2H), 0.90 (d, J = 6.6
Hz, 6H) 30 N-(4-{[2-(2- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 8.90 (ESI(+)) thienyl)ethyl]carbamoyl} (s, 1H), 8.46 (t, J =
5.6 Hz, 1H), 8.41 (s, m/e 407 phenyl)-3,4-dihydro-2,7- 1H), 8.34
(d, J = 5.0 Hz, 1H), 7.74-7.77 (m, (M + H).sup.+
naphthyridine-2(1H)- 2H), 7.55-7.58 (m, 2H), 7.33 (dd, J = 5.0,
carboxamide 1.2 Hz, 1H), 7.22 (d, J = 5.0 Hz, 1H), 6.96 (dd, J =
5.1, 3.4 Hz, 1H), 6.91 (d, J = 3.9 Hz, 1H), 4.69-4.70 (bs, 2H),
3.74 (t, J = 5.8 Hz, 2H), 3.44-3.52 (m, 2H), 3.05 (t, J = 7.2 Hz,
2H), 2.88 (t, J = 5.8 Hz, 2H)
Example 9
N-{5-[(3-phenylpropyl)carbamoyl]pyridin-2-yl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide
Example 9A
methyl
6-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)nicotinate
[0897] In a 500 mL round bottom flask was mixed at room temperature
triphosgene (0.722 g, 2.432 mmol) in anhydrous dichloromethane (50
mL). To this solution was added dropwise over 15 minutes a slurry
of methyl 6-aminonicotinate (1.00 g, 6.57 mmol) and
diisopropylethylamine (1.263 ml, 7.23 mmol) in anhydrous
dichloromethane (40 mL). The mixture was stirred overnight at room
temperature and a solution of 1,2,3,4-tetrahydroisoquinoline (0.834
ml, 6.57 mmol) and diisopropylethylamine (1.263 ml, 7.23 mmol) in
anhydrous dichloromethane (40 mL) was added in one portion. The
reaction mixture was stirred at room temperature overnight, the
solvents were evaporated and the title compound was isolated by
normal-phase flash chromatography.
Example 9B
6-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)nicotinic acid
[0898] The title compound was prepared as described in Example 1B,
substituting methyl
6-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)nicotinate for
methyl
4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoate.
Example 9C
N-{5-[(3-phenylpropyl)carbamoyl]pyridin-2-yl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide
[0899] The title compound was prepared as described in Example 1C,
substituting 3-phenylpropan-1-amine for 3-methylbutan-1-amine and
6-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)nicotinic acid for
4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoic acid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.54 (s, 1H), 8.71
(d, J=2.4 Hz, 1H), 8.47 (t, J=5.5 Hz, 1H), 8.11 (dd, J=8.8, 2.4 Hz,
1H), 7.87 (d, J=8.8 Hz, 1H), 7.18-7.29 (m, 9H), 4.67-4.68 (bs, 2H),
3.73 (t, J=5.9 Hz, 2H), 3.24-3.33 (m, 2H), 2.86 (t, J=5.8 Hz, 2H),
2.64 (t, J=7.6 Hz, 2H), 1.83 (p, J=7.3 Hz, 2H); (ESI(-)) m/e 413
(M-H).sup.-.
Example 10
N-{5-[(3-methylbutyl)carbamoyl]pyridin-2-yl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide
[0900] The title compound was prepared as described in Example 1C,
substituting
6-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)nicotinic acid for
4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoic acid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.54 (s, 1H), 8.71
(d, J=2.4 Hz, 1H), 8.40 (t, J=5.5 Hz, 1H), 8.10 (dd, J=8.8, 2.4 Hz,
1H), 7.87 (d, J=8.8 Hz, 1H), 7.18 (s, 4H), 4.67-4.68 (bs, 2H), 3.73
(t, J=5.9 Hz, 2H), 3.23-3.31 (m, 2H), 2.85 (t, J=5.8 Hz, 2H),
1.57-1.67 (m, 1H), 1.42 (q, J=7.1 Hz, 2H), 0.90 (d, J=6.6 Hz, 6H);
(ESI(-)) m/e 365 (M-H).sup.-.
Example 18
N-{6-[(3-methylbutyl)carbamoyl]pyridin-3-yl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide
Example 18A
methyl
5-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)picolinate
[0901] The title compound was prepared as described in Example 9A,
substituting methyl 5-aminopicolinate for methyl
6-aminonicotinate.
Example 18B
5-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)picolinic acid
[0902] The title compound was prepared as described in Example 1B,
substituting methyl
5-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)picolinate for
methyl
4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoate.
Example 18C
N-{6-[(3-methylbutyl)carbamoyl]pyridin-3-yl}-3,4-dihydroisoquinoline-2(1H)-
-carboxamide
[0903] The title compound was prepared as described in Example 1C,
substituting
5-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)picolinic acid for
4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoic acid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.05 (s, 1H), 8.76
(d, J=2.5 Hz, 1H), 8.55 (t, J=6.0 Hz, 1H), 8.07 (dd, J=8.5, 2.5 Hz,
1H), 7.92 (d, J=8.5 Hz, 1H), 7.19-7.21 (m, 4H), 4.67-4.68 (bs, 2H),
3.73 (t, J=5.8 Hz, 2H), 3.26-3.33 (m, 2H), 2.88 (t, J=5.8 Hz, 2H),
1.53-1.63 (m, 1H), 1.42 (q, J=7.1 Hz, 2H), 0.89 (d, J=6.6 Hz, 6H);
(ESI(-)) m/e 365 (M-H).sup.-.
Example 19
N-(5-{[2-(2-thienyl)ethyl]carbamoyl}pyridin-2-yl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide
[0904] The title compound was prepared as described in Example 1C,
substituting 2-(thiophen-2-yl)ethanamine for 3-methylbutan-1-amine
and 6-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)nicotinic acid
for 4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoic acid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.56 (s, 1H), 8.72
(d, J=2.4 Hz, 1H), 8.64 (t, J=5.5 Hz, 1H), 8.10 (dd, J=8.8, 2.4 Hz,
1H), 7.88 (d, J=8.8 Hz, 1H), 7.34 (dd, J=5.0, 1.2 Hz, 1H), 7.18 (s,
4H), 6.96 (dd, J=5.1, 3.4 Hz, 1H), 6.92 (d, J=3.4 Hz, 1H),
4.67-4.68 (bs, 2H), 3.74 (t, J=5.8 Hz, 2H), 3.47-3.52 (m, 2H), 3.07
(t, J=7.1 Hz, 2H), 2.86 (t, J=5.8 Hz, 2H); (ESI(-)) m/e 405
(M-H).sup.-.
Example 21
N-{6-[(3-phenylpropyl)carbamoyl]pyridin-3-yl}-3,4-dihydroisoquinoline-2(1H-
)-carboxamide
[0905] The title compound was prepared as described in Example 1C,
substituting 3-phenylpropan-1-amine for 3-methylbutan-1-amine and
5-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)picolinic acid for
4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoic acid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.06 (s, 1H), 8.77
(d, J=2.5 Hz, 1H), 8.66 (t, J=6.0 Hz, 1H), 8.07 (dd, J=8.6, 2.5 Hz,
1H), 7.93 (d, J=8.5 Hz, 1H), 7.25-7.30 (m, 2H), 7.14-7.24 (m, 7H),
4.67-4.68 (bs, 2H), 3.74 (t, J=5.8 Hz, 2H), 3.26-3.34 (m, 2H), 2.88
(t, J=5.8 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H), 1.83 (p, J=7.3 Hz, 2H);
(ESI(+)) m/e 415 (M+H).sup.+.
Example 22
N-(6-{[2-(2-thienyl)ethyl]carbamoyl}pyridin-3-yl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide
[0906] The title compound was prepared as described in Example 1C,
substituting 2-(thiophen-2-yl)ethanamine for 3-methylbutan-1-amine
and 5-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)picolinic acid
for 4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoic acid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.07 (s, 1H), 8.77
(d, J=2.0 Hz, 1H), 8.76 (t, J=6.3 Hz, 1H), 8.08 (dd, J=8.5, 2.5 Hz,
1H), 7.94 (d, J=8.5 Hz, 1H), 7.33 (dd, J=5.0, 1.2 Hz, 1H), 7.20 (s,
4H), 6.95 (dd, J=5.0, 3.4 Hz, 1H), 6.90-6.92 (m, 1H), 4.67-4.68
(bs, 2H), 3.74 (t, J=5.8 Hz, 2H), 3.54 (q, J=6.8 Hz, 2H), 3.07 (t,
J=7.2 Hz, 2H), 2.88 (t, J=5.8 Hz, 2H); (ESI(+)) m/e 407
(M+H).sup.+.
Example 26
N-[4-(2-oxo-2-{[2-(2-thienyl)ethyl]amino}ethyl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide
Example 26A
ethyl
2-(4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)phenyl)acetate
[0907] The title compound was prepared as described in Example 1A,
substituting ethyl 2-(4-isocyanatophenyl)acetate for methyl
4-isocyanatobenzoate.
Example 26B
2-(4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)phenyl)acetic
acid
[0908] The title compound was prepared as described in Example 1B,
substituting ethyl
2-(4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)phenyl)acetate
for methyl
4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoate.
Example 26C
N-[4-(2-oxo-2-{[2-(2-thienyl)ethyl]amino}ethyl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide
[0909] The title compound was prepared as described in Example 1C,
substituting 2-(thiophen-2-yl)ethanamine for 3-methylbutan-1-amine
and
2-(4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)phenyl)acetic
acid for 4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoic
acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.51 (s, 1H),
8.08-8.12 (m, 1H), 7.36-7.39 (m, 2H), 7.32 (dd, J=5.1, 1.2 Hz, 1H),
7.18 (s, 4H), 7.07-7.11 (m, 2H), 6.94 (dd, J=5.1, 3.4 Hz, 1H),
6.83-6.85 (m, 1H), 4.62-4.63 (bs, 2H), 3.69 (t, J=5.8 Hz, 2H),
3.31-3.33 (bs, 2H), 3.25-3.31 (m, 2H), 2.91 (t, J=7.1 Hz, 2H), 2.84
(t, J=5.8 Hz, 2H); (ESI(+)) m/e 420 (M+H).sup.+.
Example 27
N-(4-{2-oxo-2-[(3-phenylpropyl)amino]ethyl}phenyl)-3,4-dihydroisoquinoline-
-2(1H)-carboxamide
[0910] The title compound was prepared as described in Example 1C,
substituting phenylpropylamine for 3-methylbutan-1-amine and
2-(4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)phenyl)acetic
acid for 4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoic
acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.51 (s, 1H),
7.97-8.01 (m, 1H), 7.37-7.40 (m, 2H), 7.24-7.28 (m, 2H), 7.15-7.18
(m, 7H), 7.11-7.15 (m, 2H), 4.62-4.63 (bs, 2H), 3.69 (t, J=5.9 Hz,
2H), 3.31-3.32 (bs, 2H), 3.02-3.07 (m, 2H), 2.84 (t, J=5.8 Hz, 2H),
2.51-2.58 (m, 2H), 1.68 (p, J=7.3 Hz, 2H); (ESI(+)) m/e 428
(M+H).sup.+.
Example 29
N-(4-{2-[(3-methylbutyl)amino]-2-oxoethyl}phenyl)-3,4-dihydroisoquinoline--
2(1H)-carboxamide
[0911] The title compound was prepared as described in Example 1C,
substituting
2-(4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)phenyl)acetic
acid for 4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoic
acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.51 (s, 1H),
7.88-7.91 (m, 1H), 7.36-7.39 (m, 2H), 7.18 (s, 4H), 7.09-7.12 (m,
2H), 4.62-4.63 (bs, 2H), 3.69 (t, J=5.9 Hz, 2H), 3.29 (s, 2H),
3.02-3.07 (m, 2H), 2.84 (t, J=5.8 Hz, 2H), 1.50-1.61 (m, 1H), 1.28
(q, J=7.1 Hz, 2H), 0.85 (d, J=6.6 Hz, 6H); (ESI(+)) m/e 380
(M+H).sup.+.
Example 31
N-{4-[(4-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide
Example 31A
N-(4-nitrophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide
[0912] The title compound was prepared as described in Example 1A,
substituting 1-isocyanato-4-nitrobenzene for methyl
4-isocyanatobenzoate.
Example 31B
N-(4-aminophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide
[0913] A 100 mL round bottom flask charged with 10% palladium on
carbon (100 mg, 0.940 mmol) catalyst was degassed and back filled
with nitrogen. To this flask was added a mixture of
N-(4-nitrophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (1.07
g, 3.60 mmol) in methanol (30 ml). The reaction was degassed and
back filled with hydrogen. The suspension was stirred overnight at
room temperature and then filtered through diatomaceous earth with
methanol washes. Concentration of the filtrate and normal-phase
flash chromatography provided the title compound.
Example 31C
N-{4-[(4-methylpentanoyl)amino]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide
[0914] The title compound was prepared as described in Example 1C,
substituting
N-(4-aminophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide for
3-methylbutan-1-amine and 4-methylpentanoic acid for
4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoic acid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.72 (s, 1H), 8.48
(s, 1H), 7.41-7.46 (m, 2H), 7.34-7.38 (m, 2H), 7.17-7.18 (m, 4H),
4.62-4.62 (bs, 2H), 3.68 (t, J=5.8 Hz, 2H), 2.84 (t, J=5.8 Hz, 2H),
2.27 (t, J=7.6 Hz, 2H), 1.49-1.61 (m, 1H), 1.44-1.51 (m, 2H), 0.89
(d, J=6.4 Hz, 6H); (ESI(+)) m/e 366 (M+H).sup.+.
TABLE-US-00003 TABLE 3 The following examples were essentially
prepared as described in Example 31, substituting the appropriate
acid for 4-methylpentanoic acid in Example 31C. Ex Name .sup.1H NMR
MS 32 N-{4-[(4- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
(ESI(+)) phenylbutanoyl)amino] ppm 9.73 (s, 1H), 8.48 (s, 1H),
7.43- m/e 414 phenyl}-3,4-dihydroisoquinoline- 7.49 (m, 2H),
7.35-7.38 (m, 2H), (M + H).sup.+ 2(1H)-carboxamide 7.27-7.31 (m,
2H), 7.20-7.23 (m, 2H), 7.14-7.20 (m, 5H), 4.61-4.62 (bs, 2H), 3.68
(t, J = 5.8 Hz, 2H), 2.84 (t, J = 5.8 Hz, 2H), 2.62 (t, J = 7.5 Hz,
2H), 2.29 (t, J = 7.4 Hz, 2H), 1.81-1.93 (m, 2H) 33 N-(4-{[3-(2-
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. (ESI(+))
thienyl)propanoyl]amino} ppm 9.82 (s, 1H), 8.49 (s, 1H), 7.43- m/e
406 phenyl)-3,4-dihydroisoquinoline- 7.45 (m, 2H), 7.36-7.39 (m,
2H), 7.30 (M + H).sup.+ 2(1H)-carboxamide (dd, J = 5.0, 1.2 Hz,
1H), 7.18-7.18 (bs, 4H), 6.93 (dd, J = 5.2, 3.4 Hz, 1H), 6.89 (d, J
= 3.8 Hz, 1H), 4.62- 4.62 (bs, 2H), 3.68 (t, J = 5.8 Hz, 2H), 3.11
(t, J = 7.4 Hz, 2H), 2.84 (t, J = 5.9 Hz, 2H), 2.64 (t, J = 7.4 Hz,
2H) 63 N-(4- .sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(+))
{[(benzyloxy)acetyl]amino} Deuterium Oxide, Temp = 90.degree. C.)
.delta. m/e 416 phenyl)-3,4-dihydroisoquinoline- ppm 7.43-7.48 (m,
2H), 7.34-7.42 (m, (M + H).sup.+ 2(1H)-carboxamide 6H), 7.28-7.33
(m, 1H), 7.15-7.20 (m, 4H), 4.61-4.64 (m, 4H), 4.06 (s, 2H), 3.68
(t, J = 5.9 Hz, 2H), 2.86 (t, J = 6.0 Hz, 2H) 64 N-(4-{[(4- .sup.1H
NMR (400 MHz, DMSO-d.sub.6/ (ESI(-)) methoxycyclohexyl)carbonyl]
Deuterium Oxide, Temp = 90.degree. C.) .delta. m/e 406
amino}phenyl)-3,4- ppm 7.40-7.48 (m, 2H), 7.34-7.36 (m, (M -
H).sup.- dihydroisoquinoline-2(1H)- 2H), 7.11-7.25 (m, 4H), 4.61
(s, 2H), carboxamide 3.68 (t, J = 6.0 Hz, 2H), 3.39 (p, J = 3.4 Hz,
1H), 2.86 (t, J = 6.0 Hz, 2H), 2.23-2.39 (m, 1H), 1.87 (dd, J =
13.6, 4.2 Hz, 2H) 65 N-(4-{[(1-acetylpiperidin-4- .sup.1H NMR (400
MHz, DMSO-d.sub.6/ (ESI(-)) yl)carbonyl]amino}phenyl)- Deuterium
Oxide, Temp = 90.degree. C.) .delta. m/e 419
3,4-dihydroisoquinoline- ppm 7.41-7.44 (m, 2H), 7.35-7.38 (m, (M -
H).sup.- 2(1H)-carboxamide 2H), 7.18 (s, 3H), 7.18 (s, 1H), 4.61
(s, 2H), 3.81-4.37 (m, 2H), 3.66-3.70 (m, 2H), 2.93-3.18 (m, 1H),
2.86 (t, J = 6.0 Hz, 2H), 2.61-2.84 (m, 1H), 2.50-2.63 (m, 1H),
2.01 (s, 3H), 1.79- 1.85 (m, 2H), 1.49-1.64 (m, 2H) 66
N-(4-{[4-oxo-4-(2- .sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(+))
thienyl)butanoyl]amino} Deuterium Oxide, Temp = 90.degree. C.)
.delta. m/e 434 phenyl)-3,4-dihydroisoquinoline- ppm 7.92 (dd, J =
3.7, 1.1 Hz, 1H), (M + H).sup.+ 2(1H)-carboxamide 7.90 (dd, J =
4.9, 1.1 Hz, 1H), 7.39- 7.43 (m, 2H), 7.35-7.37 (m, 2H), 7.23 (dd,
J = 4.9, 3.7 Hz, 1H), 7.13-7.19 (m, 4H), 4.61 (s, 2H), 3.68 (t, J =
6.0 Hz, 2H), 3.25 (t, J = 6.7 Hz, 2H), 2.86 (t, J = 6.0 Hz, 2H),
2.70 (t, J = 6.7 Hz, 2H) 67 N-(4-{[3- .sup.1H NMR (400 MHz,
DMSO-d.sub.6/ (ESI(+)) (phenylsulfonyl)propanoyl] Deuterium Oxide,
Temp = 90.degree. C.) .delta. m/e 464 amino}phenyl)-3,4- ppm
7.88-7.94 (m, 2H), 7.71-7.76 (m, (M + H).sup.+
dihydroisoquinoline-2(1H)- 1H), 7.63-7.68 (m, 2H), 7.31-7.37 (m,
carboxamide 4H), 7.14-7.21 (m, 4H), 4.61 (s, 2H), 3.68 (t, J = 5.9
Hz, 2H), 3.57 (t, J = 7.3 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H),
2.66-2.70 (m, 2H) 68 N-{4-[((2R)-2,3-dihydro-1- .sup.1H NMR (400
MHz, DMSO-d.sub.6/ (ESI(+)) benzofuran-2- Deuterium Oxide, Temp =
90.degree. C.) .delta. m/e 414 ylcarbonyl)amino]phenyl}- ppm
7.47-7.49 (m, 2H), 7.39-7.41 (m, (M + H).sup.+
3,4-dihydroisoquinoline- 2H), 7.22-7.25 (m, 1H), 7.15-7.20 (m,
2(1H)-carboxamide and N-{4- 4H), 7.11-7.16 (m, 1H), 6.86-6.90 (m,
[((2S)-2,3-dihydro-1- 2H), 5.26 (dd, J = 10.1, 6.8 Hz, 1H),
benzofuran-2- 4.61 (s, 2H), 3.68 (t, J = 5.9 Hz, 2H),
ylcarbonyl)amino]phenyl}- 3.52 (dd, J = 16.0, 10.1 Hz, 1H), 3.38
3,4-dihydroisoquinoline- (dd, J = 15.9, 6.9 Hz, 1H), 2.86 (t, J =
2(1H)-carboxamide 6.0 Hz, 2H) 69 N-{4-[((3R)-3- .sup.1H NMR (400
MHz, DMSO-d.sub.6/ (ESI(+)) methylpentanoyl)amino] Deuterium Oxide,
Temp = 90.degree. C.) .delta. m/e 366
phenyl}-3,4-dihydroisoquinoline- ppm 7.40-7.43 (m, 2H), 7.34-7.37
(m, (M + H).sup.+ 2(1H)-carboxamide and N-{4- 2H), 7.14-7.21 (m,
4H), 4.61 (s, 2H), [((3S)-3- 3.68 (t, J = 6.0 Hz, 2H), 2.86 (t, J =
methylpentanoyl)amino] 6.0 Hz, 2H), 2.26 (dd, J = 13.8, 6.2
phenyl}-3,4-dihydroisoquinoline- Hz, 1H), 2.10 (dd, J = 13.8, 7.8
Hz, 2(1H)-carboxamide 1H), 1.82-1.95 (m, 1H), 1.33-1.44 (m, 1H),
1.18-1.29 (m, 1H), 0.92 (d, J = 6.7 Hz, 3H), 0.88 (t, J = 7.4 Hz,
3H) 70 N-{4-[(2,2- .sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(-))
dimethylbutanoyl)amino] Deuterium Oxide, Temp = 90.degree. C.)
.delta. m/e 364 phenyl}-3,4-dihydroisoquinoline- ppm 7.40-7.44 (m,
2H), 7.34-7.38 (m, (M - H).sup.- 2(1H)-carboxamide 2H), 7.18 (s,
4H), 4.62 (s, 2H), 3.68 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz,
2H), 1.61 (q, J = 7.4 Hz, 2H), 1.18 (s, 6H), 0.83 (t, J = 7.4 Hz,
3H) 71 N-{4-[(3,3- .sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(+))
dimethylbutanoyl)amino] Deuterium Oxide, Temp = 90.degree. C.)
.delta. m/e 366 phenyl}-3,4-dihydroisoquinoline- ppm 7.40-7.43 (m,
2H), 7.34-7.37 (m, (M + H).sup.+ 2(1H)-carboxamide 2H), 7.13-7.22
(m, 4H), 4.61 (s, 2H), 3.68 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0
Hz, 2H), 2.17 (s, 2H), 1.03 (s, 9H) 72 N-[4- .sup.1H NMR (400 MHz,
DMSO-d.sub.6/ (ESI(-)) (heptanoylamino)phenyl]-3,4- Deuterium
Oxide, Temp = 90.degree. C.) .delta. m/e 378
dihydroisoquinoline-2(1H)- ppm 7.39-7.44 (m, 2H), 7.33-7.38 (m, (M
- H).sup.- carboxamide 2H), 7.14-7.22 (m, 4H), 4.61 (s, 2H), 3.68
(t, J = 5.9 Hz, 2H), 2.86 (t, J = 6.0 Hz, 2H), 2.27 (t, J = 7.4 Hz,
2H), 1.60 (p, J = 7.1 Hz, 2H), 1.27-1.37 (m, 6H), 0.84-0.90 (m, 3H)
73 N-{4-[(4,4,4- .sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(-))
trifluorobutanoyl)amino] Deuterium Oxide, Temp = 90.degree. C.)
.delta. m/e 390 phenyl}-3,4-dihydroisoquinoline- ppm 7.37-7.41 (m,
4H), 6.95-7.22 (m, (M - H).sup.- 2(1H)-carboxamide 4H), 4.62 (s,
2H), 3.68 (t, J = 6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 2H), 2.53- 2.65
(m, 4H) 74 N-(4-{[(2- .sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(+))
methoxyethoxy)acetyl]amino} Deuterium Oxide, Temp = 90.degree. C.)
.delta. m/e 384 phenyl)-3,4- ppm 7.44-7.47 (m, 2H), 7.38-7.41 (m,
(M + H).sup.+ dihydroisoquinoline-2(1H)- 2H), 7.11-7.22 (m, 4H),
4.62 (s, 2H), carboxamide 4.04 (s, 2H), 3.66-3.71 (m, 4H), 3.54-
3.57 (m, 2H), 3.32 (s, 3H), 2.86 (t, J = 6.0 Hz, 2H) 75
N-{4-[((3R)-tetrahydrofuran- .sup.1H NMR (400 MHz, DMSO-d.sub.6/
(ESI(+)) 3-ylcarbonyl)amino]phenyl}- Deuterium Oxide, Temp =
90.degree. C.) .delta. m/e 366 3,4-dihydroisoquinoline- ppm
7.41-7.44 (m, 2H), 7.36-7.39 (m, (M + H).sup.+ 2(1H)-carboxamide
and N-{4- 2H), 7.17 (s, 4H), 4.61 (s, 2H), 3.93
[((3S)-tetrahydrofuran-3- (t, J = 8.1 Hz, 1H), 3.65-3.83 (m, 5H),
ylcarbonyl)amino]phenyl}- 3.09-3.17 (m, 1H), 2.86 (t, J = 6.0 Hz,
3,4-dihydroisoquinoline- 2H), 2.00-2.12 (m, 2H) 2(1H)-carboxamide
76 N-(4-{[3- .sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(+))
(methylthio)propanoyl]amino} Deuterium Oxide, Temp = 90.degree. C.)
.delta. m/e 370 phenyl)-3,4- ppm 7.32-7.50 (m, 4H), 7.11-7.26 (m,
(M + H).sup.+ dihydroisoquinoline-2(1H)- 4H), 4.61 (s, 2H), 3.68
(t, J = 6.0 Hz, carboxamide 2H), 2.86 (t, J = 6.0 Hz, 2H), 2.74-
2.78 (m, 2H), 2.59 (t, J = 7.0 Hz, 2H), 2.09 (s, 3H) 77 N-{4-
.sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(+))
[(cyclopentylacetyl)amino] Deuterium Oxide, Temp = 90.degree. C.)
.delta. m/e 378 phenyl}-3,4-dihydroisoquinoline- ppm 7.40-7.43 (m,
2H), 7.34-7.37 (m, (M + H).sup.+ 2(1H)-carboxamide 2H), 7.14-7.21
(m, 4H), 4.61 (s, 2H), 3.68 (t, J = 5.9 Hz, 2H), 2.86 (t, J = 6.0
Hz, 2H), 2.24-2.29 (m, 3H), 1.72- 1.80 (m, 2H), 1.48-1.64 (m, 4H),
1.17-1.26 (m, 2H) 78 N-{4- .sup.1H NMR (400 MHz, DMSO-d.sub.6/
(ESI(+)) [(cyclohexylcarbonyl)amino] Deuterium Oxide, Temp =
90.degree. C.) .delta. m/e XXX phenyl}-3,4- ppm 7.41-7.44 (m, 2H),
7.33-7.36 (m, (M + H).sup.+ dihydroisoquinoline-2(1H)- 2H),
7.13-7.22 (m, 4H), 4.61 (s, 2H), carboxamide 3.68 (t, J = 5.9 Hz,
2H), 2.86 (t, J = 6.0 Hz, 2H), 2.27-2.35 (m, 1H), 1.70- 1.82 (m,
4H), 1.62-1.67 (m, 1H), 1.38-1.49 (m, 2H), 1.14-1.34 (m, 3H) 79
N-{4- .sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(-))
[(cyclohexylacetyl)amino] Deuterium Oxide, Temp = 90.degree. C.)
.delta. m/e 390 phenyl}-3,4-dihydroisoquinoline- ppm 7.40-7.43 (m,
2H), 7.34-7.36 (m, (M - H).sup.- 2(1H)-carboxamide 2H), 7.14-7.21
(m, 4H), 4.61 (s, 2H), 3.68 (t, J = 5.9 Hz, 2H), 2.86 (t, J = 6.0
Hz, 2H), 2.16 (d, J = 6.9 Hz, 2H), 1.58-1.80 (m, 6H), 1.11-1.30 (m,
3H), 0.95-1.06 (m, 2H) 80 N-[4-(benzoylamino)phenyl]- .sup.1H NMR
(400 MHz, DMSO-d.sub.6/ (ESI(+)) 3,4-dihydroisoquinoline- Deuterium
Oxide, Temp = 90.degree. C.) .delta. m/e 372 2(1H)-carboxamide ppm
7.92-7.94 (m, 2H), 7.58-7.63 (m, (M + H).sup.+ 2H), 7.54-7.58 (m,
1H), 7.48-7.53 (m, 2H), 7.42-7.45 (m, 2H), 7.18 (s, 4H), 4.63 (s,
2H), 3.70 (t, J = 5.9 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H) 81 N-{4-
.sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(+)) [(phenylacetyl)amino]
Deuterium Oxide, Temp = 90.degree. C.) .delta. m/e 386
phenyl}-3,4-dihydroisoquinoline- ppm 7.25-7.43 (m, 8H), 7.20-7.28
(m, (M + H).sup.+ 2(1H)-carboxamide 1H), 7.17 (s, 4H), 4.61 (s,
2H), 3.68 (t, J = 5.9 Hz, 2H), 3.61 (s, 2H), 2.84- 2.87 (m, 2H) 82
N-(4-{[3-(4- .sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(+))
aminophenyl)propanoyl]amino} Deuterium Oxide, Temp = 90.degree. C.)
.delta. m/e 415 phenyl)-3,4- ppm 7.33-7.41 (m, 4H), 7.16-7.21 (m,
(M + H).sup.+ dihydroisoquinoline-2(1H)- 2H), 7.15-7.20 (m, 4H),
6.95-6.99 (m, carboxamide 2H), 4.61 (s, 2H), 3.68 (t, J = 5.9 Hz,
2H), 2.87-2.91 (m, 2H), 2.84-2.87 (m, 2H), 2.55-2.60 (m, 2H) 83
N-[4-(3-furoylamino)phenyl]- .sup.1H NMR (400 MHz, DMSO-d.sub.6/
(ESI(-)) 3,4-dihydroisoquinoline- Deuterium Oxide, Temp =
90.degree. C.) .delta. m/e 360 2(1H)-carboxamide ppm 8.25 (dd, J =
1.6, 0.8 Hz, 1H), (M - H).sup.- 7.68 (t, J = 1.7 Hz, 1H), 7.52-7.55
(m, 2H), 7.41-7.43 (m, 2H), 7.18 (s, 4H), 6.94 (dd, J = 1.9, 0.9
Hz, 1H), 4.63 (s, 2H), 3.69 (t, J = 5.9 Hz, 2H), 2.87 (t, J = 6.0
Hz, 2H) 84 N-{4-[(2,5-dimethyl-3- .sup.1H NMR (400 MHz,
DMSO-d.sub.6/ (ESI(-)) furoyl)amino]phenyl}-3,4- Deuterium Oxide,
Temp = 90.degree. C.) .delta. m/e 388 dihydroisoquinoline-2(1H)-
ppm 7.51-7.54 (m, 2H), 7.38-7.41 (m, (M - H).sup.- carboxamide 2H),
7.14-7.21 (m, 4H), 6.53-6.54 (m, 1H), 4.62 (s, 2H), 3.69 (t, J =
6.0 Hz, 2H), 2.86 (t, J = 6.0 Hz, 2H), 2.48 (s, 3H), 2.25 (s, 3H)
85 N-{4-[(3- .sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(+))
thienylcarbonyl)amino] Deuterium Oxide, Temp = 90.degree. C.)
.delta. m/e 378 phenyl}-3,4-dihydroisoquinoline- ppm 8.24 (dd, J =
2.9, 1.4 Hz, 1H), (M + H).sup.+ 2(1H)-carboxamide 7.61 (dd, J =
5.0, 1.4 Hz, 1H), 7.54- 7.59 (m, 3H), 7.41-7.44 (m, 2H), 7.18 (s,
4H), 4.63 (s, 2H), 3.70 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz,
2H) 86 N-{4-[(1H-pyrrol-2- .sup.1H NMR (400 MHz, DMSO-d.sub.6/
(ESI(-)) ylcarbonyl)amino]phenyl}- Deuterium Oxide, Temp =
90.degree. C.) .delta. m/e 359
3,4-dihydroisoquinoline- ppm 7.54-7.56 (m, 2H), 7.39-7.42 (m, (M -
H).sup.- 2(1H)-carboxamide 2H), 7.16-7.20 (m, 4H), 6.94-6.98 (m,
2H), 6.16 (dd, J = 3.7, 2.5 Hz, 1H), 4.63 (s, 2H), 3.69 (t, J = 5.9
Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H) 87 N-{4-[(1,3-miazol-5- .sup.1H
NMR (400 MHz, DMSO-d.sub.6/ (ESI(+)) ylcarbonyl)amino]phenyl}-
Deuterium Oxide, Temp = 90.degree. C.) .delta. m/e 379
3,4-dihydroisoquinoline- ppm 9.19-9.20 (m, 1H), 8.59-8.60 (m, (M +
H).sup.+ 2(1H)-carboxamide 1H), 7.53-7.56 (m, 2H), 7.44-7.47 (m,
2H), 7.13-7.23 (m, 4H), 4.63 (s, 2H), 3.70 (t, J = 5.9 Hz, 2H),
2.87 (t, J = 5.9 Hz, 2H) 88 N-{4-[(1H-pyrazol-5- .sup.1H NMR (400
MHz, DMSO-d.sub.6/ (ESI(+)) ylcarbonyl)amino]phenyl}- Deuterium
Oxide, Temp = 90.degree. C.) .delta. m/e 362
3,4-dihydroisoquinoline- ppm 7.71-7.83 (m, 1H), 7.58-7.61 (m, (M +
H).sup.+ 2(1H)-carboxamide 2H), 7.41-7.44 (m, 2H), 7.18 (s, 4H),
6.70-6.85 (m, 1H), 4.63 (s, 2H), 3.70 (t, J = 5.9 Hz, 2H), 2.87 (t,
J = 6.0 Hz, 2H) 89 N-{4-[(1H-pyrazol-4- .sup.1H NMR (400 MHz,
DMSO-d.sub.6/ (ESI(-)) ylcarbonyl)amino]phenyl}- Deuterium Oxide,
Temp = 90.degree. C.) .delta. m/e 360 3,4-dihydroisoquinoline- ppm
7.87-8.40 (m, 2H), 7.53-7.55 (m, (M - H).sup.- 2(1H)-carboxamide
2H), 7.39-7.42 (m, 2H), 7.18 (s, 4H), 4.63 (s, 2H), 3.69 (t, J =
5.9 Hz, 2H), 2.87 (t, J = 5.9 Hz, 2H) 90 N-{4-[(1,2-oxazol-5-
.sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(-))
ylcarbonyl)amino]phenyl}- Deuterium Oxide, Temp = 90.degree. C.)
.delta. m/e 361 3,4-dihydroisoquinoline- ppm 8.67 (d, J = 1.8 Hz,
1H), 7.57- (M - H).sup.- 2(1H)-carboxamide 7.60 (m, 2H), 7.45-7.48
(m, 2H), 7.18 (s, 4H), 7.13 (d, J = 2.0 Hz, 1H), 4.63 (s, 2H), 3.70
(t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H) 91 N-{4-[(pyridin-2-
.sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(+))
ylacetyl)amino]phenyl}-3,4- Deuterium Oxide, Temp = 90.degree. C.)
.delta. m/e 387 dihydroisoquinoline-2(1H)- ppm 8.62-8.65 (m, 1H),
8.06-8.12 (m, (M + H).sup.+ carboxamide 1H), 7.64-7.69 (m, 1H),
7.54-7.59 (m, 1H), 7.42-7.46 (m, 2H), 7.37-7.41 (m, 2H), 7.14-7.21
(m, 4H), 4.61 (s, 2H), 3.68 (t, J = 6.0 Hz, 2H), 2.91 (s, 2H), 2.86
(t, J = 6.0 Hz, 2H) 92 N-{4-[(N,N-dimethyl-beta- .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. (ESI(+)) alanyl)amino]phenyl}-3,4- ppm
9.89 (s, 1H), 8.49 (s, 1H), 7.44 m/e 367 dihydroisoquinoline-2(1H)-
(m, 2H), 7.37 (m, 2H), 7.17 (m, 4H), (M + H).sup.+ carboxamide 4.62
(bs, 2H), 3.68 (t, J = 5.9 Hz, 2H), 2.84 (t, J = 5.8 Hz, 2H), 2.57
(t, J = 7.0 Hz, 2H), 2.42 (t, J = 7.0 Hz, 2H), 2.19(s, 6H) 93
N-(4-{[3-(piperidin-1- .sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(+))
yl)propanoyl] amino}phenyl)- Deuterium Oxide, Temp = 90.degree. C.)
.delta. m/e 407 3,4-dihydroisoquinoline- ppm 7.41-7.44 (m, 4H),
7.14-7.19 (m, (M + H).sup.+ 2(1H)-carboxamide 4H), 4.62 (s, 2H),
3.68 (t, J = 6.0 Hz, 2H), 3.38 (t, J = 7.0 Hz, 2H), 2.92- 3.59 (m,
4H), 2.86 (t, J = 6.0 Hz, 2H), 2.81 (t, J = 7.1 Hz, 2H), 1.29-2.09
(m, 6H) 94 N-{4-[(morpholin-4- .sup.1H NMR (400 MHz, DMSO-d.sub.6/
(ESI(+)) ylacetyl)amino]phenyl}-3,4- Deuterium Oxide, Temp =
90.degree. C.) .delta. m/e 395 dihydroisoquinoline-2(1H)- ppm
7.25-7.50 (m, 4H), 7.11-7.24 (m, (M + H).sup.+ carboxamide 4H),
4.62 (s, 2H), 3.96-3.97 (m, 2H), 3.86-3.89 (m, 4H), 3.69 (t, J =
6.0 Hz, 2H), 3.26-3.29 (m, 4H), 2.86 (t, J = 6.0 Hz, 2H) 95
N-(4-{[3-(morpholin-4- .sup.1H NMR (400 MHz, DMSO-d.sub.6/ (ESI(-))
yl)propanoyl] amino}phenyl)- Deuterium Oxide, Temp = 90.degree. C.)
.delta. m/e 407 3,4-dihydroisoquinoline- ppm 7.39-7.46 (m, 4H),
7.13-7.24 (m, (M - H).sup.- 2(1H)-carboxamide 4H), 4.61-4.63 (m,
2H), 3.82-3.89 (m, 4H), 3.69 (t, J = 5.8 Hz, 2H), 3.44 (t, J = 7.0
Hz, 2H), 3.25-3.30 (m, 4H), 2.80-2.89 (m, 4H) 96
N-(4-{[3-(4-methylpiperazin- .sup.1H NMR (400 MHz, DMSO-d.sub.6/
(ESI(+)) 1-yl)propanoyl]amino}phenyl)- Deuterium Oxide, Temp =
90.degree. C.) .delta. m/e 422 3,4-dihydroisoquinoline- ppm
7.37-7.43 (m, 4H), 7.14-7.22 (m, (M + H).sup.+ 2(1H)-carboxamide
4H), 4.61 (s, 2H), 3.68 (t, J = 6.0 Hz, 2H), 3.19-3.26 (m, 4H),
2.96-3.09 (m, 6H), 2.86 (t, J = 6.0 Hz, 2H), 2.77 (s, 3H), 2.61 (t,
J = 6.9 Hz, 2H) Some products were purified by flash chromatography
while others were purified by reverse-phase HPLC; accordingly, some
examples were isolated as trifluoroacetic acid salts.
Example 34
N-[4-(1-isobutyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-car-
boxamide
Example 34A
N-(4-bromophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide
[0915] The title compound was prepared as described in Example 1A,
substituting 1-bromo-4-isocyanatobenzene for methyl
4-isocyanatobenzoate.
Example 34B
N-[4-(1-isobutyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-car-
boxamide
[0916] In a 5 mL microwave vial were mixed
N-(4-bromophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (75 mg,
0.226 mmol),
1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyra-
zole (61 mg, 0.25 mmol), sodium carbonate (50.4 mg, 0.476 mmol),
and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(5.55 mg, 6.79 .mu.mol) in tetrahydrofuran (2 ml)/water (1
ml)/methanol (0.333 ml). The solution was put through three
vacuum/nitrogen purge cycles; and the reaction vial was sealed and
heated overnight at 80.degree. C. The reaction mixture was diluted
with ethyl acetate, and washed with water and saturated sodium
chloride solution. Concentration of the combined organic layers
gave a residue which was purified by normal-phase flash
chromatography to provide the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.56 (s, 1H), 8.04 (d, J=0.8 Hz, 1H),
7.79 (d, J=0.8 Hz, 1H), 7.43-7.49 (m, 4H), 7.15-7.22 (m, 4H),
4.64-4.64 (bs, 2H), 3.90 (d, J=7.2 Hz, 2H), 3.70 (t, J=5.9 Hz, 2H),
2.85 (t, J=5.8 Hz, 2H), 2.07-2.18 (m, 1H), 0.86 (d, J=6.7 Hz, 6H);
(ESI(+)) m/e 375 (M+H).sup.+.
Example 35
N-[4-(1-propyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide
[0917] The title compound was prepared as described in Example 34B,
substituting
1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
for
1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.56 (s, 1H), 8.06
(d, J=0.8 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H), 7.42-7.49 (m, 4H),
7.17-7.22 (m, 4H), 4.64-4.64 (bs, 2H), 4.02-4.07 (m, 2H), 3.70 (t,
J=5.9 Hz, 2H), 2.85 (t, J=5.8 Hz, 2H), 1.76-1.85 (m, 2H), 0.85 (t,
J=7.4 Hz, 3H); (ESI(+)) m/e 361 (M+H).sup.+.
Example 36
N-{4-[1-((2R)-2-hydroxypropyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquino-
line-2(1H)-carboxamide
[0918] The title compound was prepared as described in Example 34B,
substituting
1-((2R)-2-hydroxypropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)--
1H-pyrazole for
1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.55 (s, 1H), 8.01
(d, J=0.8 Hz, 1H), 7.79 (d, J=0.8 Hz, 1H), 7.42-7.49 (m, 4H),
7.17-7.23 (m, 4H), 4.92-4.94 (bs, 1H), 4.64-4.64 (bs, 2H),
3.99-4.00 (m, 3H), 3.70 (t, J=5.9 Hz, 2H), 2.85 (t, J=5.8 Hz, 2H),
1.04-1.06 (m, 3H); (ESI(-)) m/e 375 (M-H).sup.-.
Example 37
N-{4-[1-(3-methylbutyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquinoline-2(-
1H)-carboxamide
[0919] The title compound was prepared as described in Example 34B,
substituting
1-isopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
for
1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-
e. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.55 (s, 1H),
8.08 (s, 1H), 7.77 (s, 1H), 7.42-7.49 (m, 4H), 7.19 (s, 4H),
4.64-4.64 (bs, 2H), 4.11 (t, J=7.2 Hz, 2H), 3.70 (t, J=5.9 Hz, 2H),
2.85 (t, J=5.8 Hz, 2H), 1.69 (q, J=7.1 Hz, 2H), 1.43-1.55 (m, 1H),
0.91 (d, J=6.6 Hz, 6H); (ESI(+)) m/e 389 (M+H).sup.+.
Example 38
N-[4-(1-benzyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide
[0920] The title compound was prepared as described in Example 34B,
substituting
1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
for
1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.56 (s, 1H), 8.17
(d, J=0.8 Hz, 1H), 7.84 (d, J=0.8 Hz, 1H), 7.43-7.49 (m, 4H),
7.32-7.38 (m, 2H), 7.24-7.31 (m, 3H), 7.19 (s, 2H), 7.19 (s, 2H),
5.32 (s, 2H), 4.63-4.64 (bs, 2H), 3.70 (t, J=5.9 Hz, 2H), 2.85 (t,
J=5.8 Hz, 2H); (ESI(+)) m/e 409 (M+H).sup.+.
Example 39
N-{4-[(1E)-5-phenylpent-1-en-1-yl]phenyl}-3,4-dihydroisoquinoline-2(1H)-ca-
rboxamide
[0921] The title compound was prepared as described in Example 34B,
substituting
1(E)-4,4,5,5-tetramethyl-2-(5-phenylpent-1-enyl)-1,3,2-dioxaborolane
for
1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.57 (s, 1H),
7.42-7.45 (m, 2H), 7.25-7.31 (m, 4H), 7.15-7.23 (m, 7H), 6.31 (d,
J=15.8 Hz, 1H), 6.18 (dt, J=15.8, 6.7 Hz, 1H), 4.63-4.63 (bs, 2H),
3.69 (t, J=5.9 Hz, 2H), 2.84 (t, J=5.8 Hz, 2H), 2.62 (t, J=7.6 Hz,
2H), 2.18 (q, J=7.1 Hz, 2H), 1.73 (p, J=7.5 Hz, 2H); (ESI(+)) m/e
397 (M+H).sup.+.
Example 40
N-[4-(1-ethyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carbox-
amide
[0922] The title compound was prepared as described in Example 34B,
substituting
1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
for
1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.55 (s, 1H), 8.07
(s, 1H), 7.78 (d, J=0.8 Hz, 1H), 7.41-7.49 (m, 4H), 7.16-7.21 (m,
4H), 4.64-4.64 (bs, 2H), 4.13 (q, J=7.2 Hz, 2H), 3.70 (t, J=5.9 Hz,
2H), 2.85 (t, J=5.8 Hz, 2H), 1.39 (t, J=7.3 Hz, 3H); (ESI(-)) m/e
345 (M-H).sup.-.
Example 41
N-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]phenyl}-3,4-dihydroisoquinoline-2-
(1H)-carboxamide
[0923] The title compound was prepared as described in Example 34B,
substituting
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethano-
l for
1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazo-
le. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.55 (s, 1H),
8.03 (d, J=0.8 Hz, 1H), 7.79 (d, J=0.8 Hz, 1H), 7.42-7.49 (m, 4H),
7.14-7.23 (m, 4H), 4.91 (t, J=5.3 Hz, 1H), 4.64-4.64 (bs, 2H), 4.13
(t, J=5.6 Hz, 2H), 3.75 (q, J=5.5 Hz, 2H), 3.70 (t, J=6.0 Hz, 2H),
2.85 (t, J=5.8 Hz, 2H); (ESI(+)) m/e 363 (M+H).sup.+.
Example 42
N-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide
[0924] The title compound was prepared as described in Example 34B,
substituting
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
for
1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.55 (s, 1H), 8.02
(s, 1H), 7.77 (s, 1H), 7.46-7.48 (m, 2H), 7.41-7.44 (m, 2H),
7.15-7.23 (m, 4H), 4.63-4.64 (bs, 2H), 3.84 (s, 3H), 3.70 (t, J=5.8
Hz, 2H), 2.85 (t, J=5.8 Hz, 2H); (ESI(-)) m/e 331 (M-H).sup.-.
Example 43
N-[4-(1-benzoyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide
[0925] In a 4 mL vial was mixed
N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide (30 mg, 0.090 mmol) in anhydrous tetrahydrofuran (1
ml). Triethylamine (0.025 ml, 0.180 mmol) and benzoyl chloride (13
mg, 0.090 mmol) were added and the reaction mixture was stirred
overnight at room temperature. The mixture was diluted with ethyl
acetate and washed with water; the separated organic layer was
concentrated and the title compound was isolated by normal-phase
flash chromatography. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 8.61 (s, 1H), 7.26-7.56 (m, 10H), 7.09-7.25 (m, 4H), 5.95-6.25
(m, 1H), 4.63-4.64 (bs, 2H), 3.95-4.35 (m, 2H), 3.80-3.87 (m, 1H),
3.70 (t, J=5.8 Hz, 2H), 3.44-3.57 (m, 2H), 2.85 (t, J=5.8 Hz, 2H);
(ESI(+)) m/e 438 (M+H).sup.+.
Example 44
N-[4-(1-butyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquino-
line-2(1H)-carboxamide
[0926] The title compound was prepared as described in Example 43,
substituting butyryl chloride for benzoyl chloride. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 8.60 (s, 1H), 7.46-7.49 (m,
2H), 7.30-7.36 (m, 2H), 7.14-7.24 (m, 4H), 6.07-6.10 (m, 1H),
4.63-4.64 (bs, 2H), 4.07-4.13 (m, 2H), 3.70 (t, J=5.9 Hz, 2H), 3.64
(dd, J=12.3, 6.2 Hz, 2H), 2.85 (t, J=5.8 Hz, 2H), 2.39-2.53 (m,
2H), 2.28-2.38 (m, 2H), 1.45-1.62 (m, 2H), 0.87-0.93 (m, 3H);
(ESI(+)) m/e 404 (M+H).sup.+.
Example 45
N-{4-[1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dih-
ydroisoquinoline-2(1H)-carboxamide
[0927] The title compound was prepared as described in Example 43,
substituting propane-2-sulfonyl chloride for benzoyl chloride.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.61 (s, 1H),
7.47-7.50 (m, 2H), 7.32-7.35 (m, 2H), 7.15-7.23 (m, 4H), 6.10-6.12
(m, 1H), 4.63-4.64 (bs, 2H), 3.94-3.96 (m, 2H), 3.70 (t, J=5.8 Hz,
2H), 3.49 (t, J=5.6 Hz, 2H), 3.34-3.44 (m, 1H), 2.85 (t, J=5.8 Hz,
2H), 2.48-2.55 (m, 2H), 1.24 (d, J=6.8 Hz, 6H); (ESI(-)) m/e 438
(M-H).sup.-.
Example 46
N-[4-(1-isobutyryl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoqu-
inoline-2(1H)-carboxamide
[0928] The title compound was prepared as described in Example 43,
substituting isobutyryl chloride for benzoyl chloride. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 8.60 (s, 1H), 7.46-7.49 (m,
2H), 7.32-7.35 (m, 2H), 7.10-7.26 (m, 4H), 6.09-6.11 (bs, 1H),
4.63-4.64 (bs, 2H), 4.01-4.24 (m, 2H), 3.66-3.71 (m, 4H), 2.91-3.06
(m, 1H), 2.85 (t, J=5.8 Hz, 2H), 2.35-2.55 (m, 2H), 0.99-1.04 (m,
6H); (ESI(+)) m/e 404 (M+H).sup.+.
Example 47
N-{4-[1-(3-methylbutanoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihy-
droisoquinoline-2(1H)-carboxamide
[0929] The title compound was prepared as described in Example 43,
substituting isopentyl chloride for benzoyl chloride. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 8.60 (s, 1H), 7.44-7.51 (m,
2H), 7.30-7.36 (m, 2H), 7.18 (s, 4H), 6.07-6.11 (m, 1H), 4.63-4.64
(bs, 2H), 4.08-4.14 (m, 2H), 3.70 (t, J=6.0 Hz, 2H), 3.62-3.71 (m,
2H), 2.85 (t, J=5.8 Hz, 2H), 2.38-2.53 (m, 2H), 2.24 (dd, J=18.6,
6.9 Hz, 2H), 1.96-2.09 (m, 1H), 0.91 (t, J=6.2 Hz, 6H); (ESI(+))
m/e 418 (M+H).sup.+.
Example 48
N-{4-[1-(methylcarbamoyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide
[0930] The title compound was prepared as described in Example 1A,
substituting methyl isocyanate for methyl 4-isocyanatobenzoate and
N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide for 1,2,3,4-tetrahydroisoquinoline. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 8.59 (s, 1H), 7.46-7.48 (m, 2H),
7.32-7.34 (m, 2H), 7.18 (s, 4H), 6.42 (q, J=4.3 Hz, 1H), 6.07-6.09
(m, 1H), 4.63-4.64 (bs, 2H), 3.92-3.94 (m, 2H), 3.70 (t, J=5.8 Hz,
2H), 3.49 (t, J=5.6 Hz, 2H), 2.85 (t, J=5.8 Hz, 2H), 2.57-2.61 (m,
3H), 2.37-2.43 (m, 2H); (ESI(+)) m/e 391 (M+H).sup.+.
Example 49
tert-butyl
4-{4-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]phenyl}-3,-
6-dihydropyridine-1(2H)-carboxylate
[0931] The title compound was prepared as described in Example 34B,
substituting tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate for
1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.60 (s, 1H),
7.46-7.49 (m, 2H), 7.31-7.34 (m, 2H), 7.17-7.20 (m, 1H), 7.18 (s,
3H), 6.05-6.08 (bs, 1H), 4.63-4.64 (bs, 2H), 3.93-3.98 (m, 2H),
3.70 (t, J=5.8 Hz, 2H), 3.50-3.54 (m, 2H), 2.85 (t, J=5.8 Hz, 2H),
2.40-2.45 (m, 2H), 1.42 (s, 9H); (ESI(-)) m/e 432 (M-H).sup.-.
Example 50
N-[4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide
[0932] The title compound was prepared as described in Example 43,
substituting acetyl chloride for benzoyl chloride. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 8.60 (s, 1H), 7.46-7.49 (m, 2H),
7.31-7.35 (m, 2H), 7.19 (s, 4H), 6.07-6.10 (m, 1H), 4.63-4.64 (bs,
2H), 4.04-4.15 (m, 2H), 3.70 (t, J=5.9 Hz, 2H), 3.60-3.66 (m, 2H),
2.85 (t, J=5.8 Hz, 2H), 2.37-2.54 (m, 2H), 2.02-2.07 (m, 3H);
(ESI(+)) m/e 376 (M+H).sup.+.
Example 51
N-{4-[1-(isobutylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihy-
droisoquinoline-2(1H)-carboxamide
[0933] The title compound was prepared as described in Example 43,
substituting 2-methylpropane-1-sulfonyl chloride for benzoyl
chloride. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.62 (s,
1H), 7.47-7.50 (m, 2H), 7.33-7.36 (m, 2H), 7.19 (s, 4H), 6.10-6.13
(m, 1H), 4.63-4.64 (bs, 2H), 3.86-3.88 (m, 2H), 3.70 (t, J=5.8 Hz,
2H), 3.40 (t, J=5.7 Hz, 2H), 2.96 (d, J=6.5 Hz, 2H), 2.85 (t, J=5.8
Hz, 2H), 2.47-2.58 (m, 2H), 2.07-2.20 (m, 1H), 1.04 (d, J=6.7 Hz,
6H); (ESI(-)) m/e 452 (M-H).sup.-.
Example 52
N-[4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquinol-
ine-2(1H)-carboxamide
[0934] In a 4 mL vial were mixed
N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide (30 mg, 0.090 mmol) and benzaldehyde (9.12 .mu.l,
0.090 mmol) in anhydrous dichloroethane (1 ml) at room temperature.
Sodium triacetoxyborohydride (26.7 mg, 0.126 mmol) was added and
the mixture was stirred overnight at room temperature. The reaction
mixture was diluted with ethyl acetate and washed with saturated
aqueous sodium bicarbonate and aqueous sodium chloride solutions.
The organic layer was dried with sodium sulfate, filtered and
concentrated to give the title compound after normal-phase flash
chromatography. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
8.58 (s, 1H), 7.44-7.46 (m, 2H), 7.22-7.38 (m, 7H), 7.18 (s, 4H),
6.02-6.08 (m, 1H), 4.62-4.64 (bs, 2H), 3.69 (t, J=6.0 Hz, 2H), 3.57
(s, 2H), 3.02-3.06 (m, 2H), 2.84 (t, J=5.9 Hz, 2H), 2.62 (t, J=5.6
Hz, 2H), 2.41-2.47 (m, 2H); (ESI(-)) m/e 422 (M-H).sup.-.
Example 53
N-{4-[1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydr-
oisoquinoline-2(1H)-carboxamide
[0935] The title compound was prepared as described in Example 43,
substituting methanesulfonyl chloride for benzoyl chloride. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.61 (s, 1H), 7.47-7.50 (m,
2H), 7.33-7.36 (m, 2H), 7.19 (s, 4H), 6.10-6.13 (m, 1H), 4.63-4.64
(bs, 2H), 3.83-3.85 (m, 2H), 3.70 (t, J=5.9 Hz, 2H), 3.36 (t, J=5.7
Hz, 2H), 2.92 (s, 3H), 2.85 (t, J=5.8 Hz, 2H), 2.54-2.60 (m, 2H);
(ESI(+)) m/e 412 (M+H).sup.+.
Example 54
N-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)-
-carboxamide
[0936] In a 5 mL round bottom flask was mixed tert-butyl
4-{4-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]phenyl}-3,6-dihydrop-
yridine-1(2H)-carboxylate (461 mg, 1.063 mmol) in dichloromethane
(5 ml). Trifluoroacetic acid (1 ml, 12.98 mmol) was added at room
temperature and the mixture was stirred for 3 hours. The solution
was concentrated, the residue was quenched with saturated sodium
bicarbonate and the product was extracted with dichloromethane. The
organic layer was dried with sodium sulfate, filtered and
concentrated to give the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.58 (s, 1H), 7.43-7.46 (m, 2H),
7.28-7.31 (m, 2H), 7.16-7.21 (m, 4H), 6.05-6.12 (m, 1H), 4.63 (s,
2H), 3.86-4.14 (m, 1H), 3.69 (t, J=5.9 Hz, 2H), 3.28 (d, J=339.1
Hz, 3H), 2.89 (t, J=5.6 Hz, 1H), 2.85 (t, J=5.9 Hz, 2H), 2.25-2.34
(m, 2H); (ESI(+)) m/e 334 (M+H).sup.+.
Example 55
N-{4-[1-(3-methylbutyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-3,4-dihydro-
isoquinoline-2(1H)-carboxamide
[0937] The title compound was prepared as described in Example 52,
substituting 4-methylpentanal for benzaldehyde. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 8.57 (s, 1H), 7.44-7.46 (m, 2H),
7.29-7.32 (m, 2H), 7.18-7.20 (m, 4H), 6.05-6.07 (m, 1H), 4.63-4.64
(bs, 2H), 3.69 (t, J=5.9 Hz, 2H), 3.02-3.04 (m, 2H), 2.85 (t, J=5.8
Hz, 2H), 2.58 (t, J=5.6 Hz, 2H), 2.40-2.45 (m, 2H), 2.35-2.40 (m,
2H), 1.55-1.66 (m, 1H), 1.33-1.41 (m, 2H), 0.89 (d, J=6.6 Hz, 6H);
(ESI(-)) m/e 402 (M-H).sup.-.
Example 56
N-[4-(5-propyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)--
carboxamide
Example 56A
N-(4-cyanophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide
[0938] The title compound was prepared as described in Example 1A,
substituting 4-isocyanatobenzonitrile for methyl
4-isocyanatobenzoate.
Example 56B
(Z)--N-(4-(N'-hydroxycarbamimidoyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide
[0939] In a 25 mL pressure tube were mixed
N-(4-cyanophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (500
mg, 1.803 mmol), hydroxylamine hydrochloride (251 mg, 3.61 mmol),
and triethylamine (1.26 ml, 9.01 mmol) in ethanol (6 ml)/water (0.5
ml). The reaction vessel was sealed and heated at 80.degree. C. for
about 3 hours. The solution was diluted with water and
dichloromethane and the separated organic layer was dried with
sodium sulfate, filtered and concentrated. Normal-phase flash
chromatography of the residue provided the title compound.
Example 56C
N-[4-(5-propyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)--
carboxamide
[0940] In a 4 mL vial were mixed
(Z)--N-(4-(N'-hydroxycarbamimidoyl)phenyl)-3,4-dihydroisoquinoline-2(1H)--
carboxamide (75 mg, 0.242 mmol), butyric acid (23 mg, 0.266 mmol),
1-hydroxybenzotriazole (18.50 mg, 0.121 mmol) and
N-methylmorpholine (0.093 ml, 0.846 mmol) in anhydrous
N,N-dimethylformamide (2 ml). To this solution was added
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (69.5
mg, 0.362 mmol) and the reaction mixture was stirred overnight at
room temperature. The resulting solution was diluted with ethyl
acetate and then washed with water, saturated aqueous sodium
bicarbonate and aqueous sodium chloride solutions. The organic
layer was dried with sodium sulfate, filtered and concentrated. The
residue was dissolved in anhydrous toluene (2 ml) and heated at
110.degree. C. for 5 hours; concentration and normal-phase flash
chromatography gave the title compound. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 8.90 (s, 1H), 7.87-7.89 (m, 2H),
7.68-7.70 (m, 2H), 7.17-7.25 (m, 4H), 4.66-4.67 (bs, 2H), 3.73 (t,
J=5.9 Hz, 2H), 2.95 (t, J=7.4 Hz, 2H), 2.87 (t, J=5.9 Hz, 2H),
1.77-1.85 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); (ESI(-)) m/e 361
(M-H).sup.-.
Example 57
N-[4-(5-benzyl-1,2,4-oxadiazol-3-yl)phenyl]-3,4-dihydroisoquinoline-2(1H)--
carboxamide
[0941] The title compound was prepared as described in Example 56C,
substituting phenylacetic acid for butyric acid in Example 56C.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 8.90 (s, 1H),
7.85-7.87 (m, 2H), 7.68-7.70 (m, 2H), 7.36-7.39 (m, 4H), 7.29-7.35
(m, 1H), 7.16-7.22 (m, 4H), 4.66-4.66 (bs, 2H), 4.41 (s, 2H), 3.72
(t, J=5.9 Hz, 2H), 2.86 (t, J=5.9 Hz, 2H); (ESI(-)) m/e 409
(M-H).sup.-.
Example 58
N-{4-[5-(3-methylbutyl)-1,2,4-oxadiazol-3-yl]phenyl}-3,4-dihydroisoquinoli-
ne-2(1H)-carboxamide
[0942] The title compound was prepared as described in Example 56C,
substituting 4-methylpentanoic acid for butyric acid. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 8.90 (s, 1H), 7.87-7.89 (m,
2H), 7.68-7.71 (m, 2H), 7.19 (s, 3H), 7.19 (s, 1H), 4.66-4.67 (bs,
2H), 3.73 (t, J=5.9 Hz, 2H), 2.97 (t, J=7.7 Hz, 2H), 2.87 (t, J=5.9
Hz, 2H), 1.66-1.71 (m, 2H), 1.59-1.67 (m, 1H), 0.93 (d, J=6.4 Hz,
6H); (ESI(-)) m/e 389 (M-H).sup.-.
Example 59
N-hexyl-3,4-dihydroisoquinoline-2(1H)-carboxamide
[0943] The title compound was prepared as described in Example 1A,
substituting 1-isocyanatohexane for methyl 4-isocyanatobenzoate.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.10-7.16 (m, 4H),
6.49 (t, J=5.4 Hz, 1H), 4.46-4.46 (bs, 2H), 3.52 (t, J=5.9 Hz, 2H),
3.00-3.05 (m, 2H), 2.75 (t, J=5.9 Hz, 2H), 1.36-1.43 (m, 2H),
1.24-1.28 (m, 6H), 0.83-0.88 (m, 3H); (ESI(+)) m/e 334
(M+H).sup.+.
Example 60
ethyl
6-[(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)amino]hexanoate
[0944] The title compound was prepared as described in Example 1A,
substituting ethyl 6-isocyanatohexanoate for methyl
4-isocyanatobenzoate. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 7.10-7.17 (m, 4H), 6.51 (t, J=5.5 Hz, 1H), 4.46-4.46 (bs, 2H),
4.03 (q, J=7.1 Hz, 2H), 3.52 (t, J=5.9 Hz, 2H), 3.00-3.05 (m, 2H),
2.75 (t, J=5.9 Hz, 2H), 2.26 (t, J=7.4 Hz, 2H), 1.52 (p, J=7.5 Hz,
2H), 1.41 (p, J=7.3 Hz, 2H), 1.20-1.29 (m, 2H), 1.16 (t, J=7.1 Hz,
3H); (ESI(+)) m/e 319 (M+H).sup.+.
Example 61
N-(4-{2-[(phenylacetyl)amino]ethyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide
Example 61A
N-(4-(cyanomethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide
[0945] The title compound was prepared as described in Example 1A,
substituting 2-(4-isocyanatophenyl)acetonitrile for methyl
4-isocyanatobenzoate.
Example 61B
N-(4-(2-aminoethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide
[0946]
N-(4-(cyanomethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide
(400 mg, 1.373 mmol) and methanol/7M ammonia-methanol (5 ml) were
added to Ra--Ni 2800, water slurry (800 mg, 13.63 mmol) in a 50 ml
pressure bottle and stirred for 18 hours at 30 psi and room
temperature. The mixture was filtered through a nylon membrane and
concentrated. The residue was purified by normal-phase flash
chromatography to give the title compound.
Example 61C
N-(4-{2-[(phenylacetyl)amino]ethyl}phenyl)-3,4-dihydroisoquinoline-2(1H)-c-
arboxamide
[0947] The title compound was prepared as described in Example 1C,
substituting
N-(4-(2-aminoethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide
for 3-methylbutan-1-amine and phenylacetic acid for
4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoic acid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.49 (s, 1H), 8.06
(t, J=5.5 Hz, 1H), 7.36-7.39 (m, 2H), 7.26-7.30 (m, 2H), 7.18-7.23
(m, 7H), 7.01-7.04 (m, 2H), 4.62-4.63 (bs, 2H), 3.69 (t, J=5.8 Hz,
2H), 3.35-3.38 (m, 2H), 3.17-3.27 (m, 2H), 2.85 (t, J=5.8 Hz, 2H),
2.63 (t, J=7.2 Hz, 2H); (ESI(+)) m/e 414 (M+H).sup.+.
Example 62
N-{4-[2-(isobutyrylamino)ethyl]phenyl}-3,4-dihydroisoquinoline-2(1H)-carbo-
xamide
[0948] The title compound was prepared as described in Example 1C,
substituting
N-(4-(2-aminoethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide
for 3-methylbutan-1-amine and isobutyric acid for
4-(1,2,3,4-tetrahydroisoquinoline-2-carboxamido)benzoic acid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.48 (s, 1H),
7.72-7.76 (m, 1H), 7.36-7.40 (m, 2H), 7.18 (s, 4H), 7.04-7.07 (m,
2H), 4.62-4.63 (bs, 2H), 3.68 (t, J=5.8 Hz, 2H), 3.18-3.24 (m, 2H),
2.84 (t, J=5.8 Hz, 2H), 2.62 (t, J=7.3 Hz, 2H), 2.31 (p, J=6.8 Hz,
1H), 0.97 (d, J=6.8 Hz, 6H); ESI(+)) m/e 366 (M+H).sup.+.
Example 97
N-[4-(trifluoromethyl)phenyl]-3,4-dihydroisoquinoline-2(1H)-carboxamide
[0949] The title compound was prepared as described in Example 1A,
substituting 1-isocyanato-4-(trifluoromethyl)benzene for methyl
4-isocyanatobenzoate. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 8.96 (s, 1H) 7.72 (d, J=8.5 Hz, 2H) 7.59 (d, J=8.5 Hz, 2H)
7.17-7.22 (m, 4H) 4.66 (s, 2H) 3.72 (t, J=6.0 Hz, 2H) 2.86 (t,
J=5.8 Hz, 2H); ESI(+)) m/e 321 (M+H).sup.+.
Example 98
N-{4-[(cyclopentylacetyl)amino]phenyl}-5-[(methylsulfonyl)amino]-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide
Example 98A
2-cyclopentyl-N-(4-nitrophenyl)acetamide
[0950] The title compound was prepared as described in Example 43,
substituting 4-nitroaniline for
N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3,4-dihydroisoquinoline-2(1H-
)-carboxamide and 2-cyclopentylacetyl chloride for benzoyl
chloride.
Example 98B
N-(4-aminophenyl)-2-cyclopentylacetamide
[0951] The title compound was prepared as described in Example 31B,
substituting 2-cyclopentyl-N-(4-nitrophenyl)acetamide for
N-(4-nitrophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide.
Example 98C
N-{4-[(cyclopentylacetyl)amino]phenyl}-5-[(methylsulfonyl)amino]-3,4-dihyd-
roisoquinoline-2(1H)-carboxamide
[0952] In a 25 mL round bottom flask were mixed
N-(4-aminophenyl)-2-cyclopentylacetamide (51 mg, 0.234 mmol),
bis(2,5-dioxopyrrolidin-1-yl) carbonate (74.8 mg, 0.292 mmol), and
anhydrous pyridine (0.019 ml, 0.234 mmol) in anhydrous acetonitrile
(1 ml). The mixture stirred for 1 hour at room temperature when
diisopropylethylamine (0.122 ml, 0.701 mmol) was added followed by
dropwise addition of a mixture of
N-(1,2,3,4-tetrahydroisoquinolin-5-yl)methanesulfonamide (60.8 mg,
0.269 mmol) in anhydrous N-methylpyrollidine (3 mL). The reaction
mixture was stirred overnight at room temperature and then diluted
with water. The resulting suspension was filtered with water washes
to give the title compound after vacuum drying. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 9.70 (d, J=9.9 Hz, 1H), 9.09 (s,
1H), 8.49 (d, J=7.8 Hz, 1H), 7.46 (m, 2H), 7.35 (m, 2H), 7.21 (m,
2H), 7.11 (m, 1H), 4.62 (s, 2H), 3.66 (t, J=5.9 Hz, 2H), 2.99 (s,
3H), 2.87 (m, 2H), 2.23 (m, 3H), 1.74 (m, 2H), 1.60 (m, 2H), 1.51
(m, 2H), 1.17 (m, 2H); (ESI(+)) m/e 471 (M+H).sup.+.
* * * * *